Title of Invention	A PROCESS FOR THE PREPARATION OF (-) 3R, 4R-TRANS-2,2-DIALKYL-3-SUBSTITUTED PHENYL-4-(HYDROXY-SUBSTITUTED PHENYL)-SUBSTITUTED CHROMANS
Abstract	This invention relates to a process for the preparation of (-) 3R, 4R - trans -2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans. The product is used as key intermediates for the preparation of tissue selective estrogens as pharmaceuticals. The product of the structure 2, where in R1 and R4 are individually hydrogen, hydroxy, halogens, C1-6 alkyl, C1-6 alkoxy, R2, R3, are individually hydrogen, C1-6 alkyl and R5 is hydrogen, halogen, nitro, cyano, C1-6 alkyl or cyclic alkyloxy, is prepared by treating 3R, 4R- trans - 2,2-dialkyl -3- substituted phenyl-4-(ω-aminoalkoxy substituted phenyl)- substituted chroman derivatives of structure 3 where in R1, R2, R3, R4 and R5 are as stated above and R6 is a methyl iodide salt of a substituted amino alkoxy group, with an inorganic base 3R, 4R- trans - 2,2-dialkyl -3- substituted phenyl-4- of formula 3 with inorganic base, , isolating the hydroxide salt and reacting the isolated hydroxide salt with cyclic amines in a high boiling solvent at a temperature in the range of 80°C to 200°C for a period of 5 minutes to 8 hrs or insitu conversion of methyliodide salt to desired compound of structure 2 using above stated methodology.

Title of Invention

A PROCESS FOR THE PREPARATION OF (-) 3R, 4R-TRANS-2,2-DIALKYL-3-SUBSTITUTED PHENYL-4-(HYDROXY-SUBSTITUTED PHENYL)-SUBSTITUTED CHROMANS

Abstract

This invention relates to a process for the preparation of (-) 3R, 4R - trans -2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans. The product is used as key intermediates for the preparation of tissue selective estrogens as pharmaceuticals. The product of the structure 2, where in R1 and R4 are individually hydrogen, hydroxy, halogens, C1-6 alkyl, C1-6 alkoxy, R2, R3, are individually hydrogen, C1-6 alkyl and R5 is hydrogen, halogen, nitro, cyano, C1-6 alkyl or cyclic alkyloxy, is prepared by treating 3R, 4R- trans - 2,2-dialkyl -3- substituted phenyl-4-(ω-aminoalkoxy substituted phenyl)- substituted chroman derivatives of structure 3 where in R1, R2, R3, R4 and R5 are as stated above and R6 is a methyl iodide salt of a substituted amino alkoxy group, with an inorganic base 3R, 4R- trans - 2,2-dialkyl -3- substituted phenyl-4- of formula 3 with inorganic base, , isolating the hydroxide salt and reacting the isolated hydroxide salt with cyclic amines in a high boiling solvent at a temperature in the range of 80°C to 200°C for a period of 5 minutes to 8 hrs or insitu conversion of methyliodide salt to desired compound of structure 2 using above stated methodology.

Full Text	Field of the Invention This invention relates to a process for the preparation of (-) 3R, 4R - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans. The product is used as key intermediates for the preparation of tissue selective estrogens as pharmaceuticals. The main objective of the present invention is to provide a process for the preparation of 3R, 4R (-) - trans - 2,2-dialkyl -3- substituted phenyl-4-(hydroxy substituted phenyl)- substituted chromans, key intermediate for the synthesis of compounds having significant medicinal properties such as contraceptives, fertility inducers, breast cancer, osteoporosis, hyper cholesteremia, estrogen replacement therapy, anti-inflammatory ,prostatic carcinoma CNS and CVS disorders. Trans - 2,2-alkyl -3- phenyl-4-(4(2-tertiary aminoethoxy phenyl)-7-methoxy chroman shown below wherein R1 and R2 are individually H or lower alkyl ,R3 and R4 are lower alkyl or forms a nitrogen heterocycle including the nitrogen atom eg. pyrrolidine or piperidine etc. (n = 1 to 4) have been found useful as contraceptives. (Figure Removed) Figure I Suprabhat Ray, Amita Tandon, Indra Dwivedy, Scott R. Wilson, James P. O'Neil , and John A. Katzenellenbogen (1994). An X-ray crystallographic study of the non-steroidal contraceptive agents Centchroman J. Med. Chem., 37, 696-700; V. P. Kamboj, A. B. Kar, S. Ray , P.K. Grover and Nitya Anand(1971). Antifertility activity of 3, 4-trans 2,2-dimethyl-3-phenyl-4-p-(ß-pyrrolidinoethoxy phenyl-7-methoxychroman, Ind. J. Exp. Biol. 9, 103. S. Ray, P.K. Grover and Nitya Anand (1971). A new synthesis of cis and trans 3-phenyl-4-(4-p-pyrrolidinocthoxy) phenyl-7-methoxy chroman, Ind. J. Chem. 9, 727. S. Ray, P.K. Grover, V.P. Kamboj, B.S. Setty, Amiya B, Kar, and Nitya Anand, (1976) Studies in Antifertility agents: Part XII- Structure activity relationship study of 3, 4-diphenyl chromenes and chromans, J. Med. Chem. 19,276. Resolution of free base of 1 wherein RI = 7-OMe; R2= Me; R3= Me, R4 and R5 = H and X = H, led to the 3R,4R (-) and 3S, 4S (+) enantiomers of 1, optionally converted into its salt of 1 wherein RI, R2, RS, R4 and RS are as defined above and X is an anion of an acid such as HC1, fumaric acid, tartaric acid etc. (Figure Remove) M. Salman, S. Ray, N Anand,. A. K. Agarwal, M. M. Singh, B.S. Setty, V.P. Kamboj (1986), Studies in antifertility agents 50: stereoselective binding of d- and 1-centchromans to estrogen receptor and their antifertility activity, J. Med. Chem. 29: 1801-1803. Back ground of the invention: Estrogen agonists as well as antagonists elicit biological activity through their binding to estrogen receptor. In case of a chiral ligand, a specific chirality favours receptor binding. Thus, d-estradiol shows many fold higher affinity towards estrogen receptor binding as compared to 1-estradiol. In the case of trans-3,4-diaryl chromans of structure 1, 3R, 4R- trans- chroman wherein RI= 7-OMe; R2=Me; R3=Me, R» and R5 = H shows 7 fold higher affinity for ER binding as compared to the 3R, 4R- form and also elicits similar order of anti-implantation activity (JMC.29, 1801-1803). It is also possible that the different enantiomers may show different biological activities and also pharmacokinetic properties. Therefore, use of single enantiomeric forms as pharmaceutical is recommended. In order to develop enantiomers of trans-3,4-diaryl chromans Figure I substituted with various amino alkoxy side chain, which is known to play a major role in deciding their antiestrogenic activities and towards development of selective estrogen receptor modulators (SERM), it was therefore, necessary to synthesize hydroxy derivatives of (3R, 4R) and (3S, 4S) enantiomers of trans-3, 4-diaryl chromans 2 which would serve as intermediate for the preparation of aminoalkoxy side chain substituted final products. The object of the present investigation was therefore to develop a process for the preparation of trans-3R, 4R 3-aryl-4-(hydroxyphenyl)- substituted chromans 2, which would serve as the key intermediate for the preparation of 3R, 4R- trans-3,4-diaryl substituted chromans variously substituted with substituted amino alkyl groups on the 4-phenyl residue. Accordingly, the present invention relates to a process for the preparation of (-) 3R, 4R - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)-substituted chromans of the structure 2, where in R1 and R4 are individually hydrogen, hydroxy, halogens, C1-6 alkyl, C1-6 alkoxy, R2, R3, are individually hydrogen, C1-6 alkyl and R5 is hydrogen, halogen, nitro, cyano, C1-6 alkyl or cyclic alkyloxy, treating 3R, 4R- trans - 2,2-dialkyl -3- substituted phenyl-4-(ω-aminoalkoxy substituted phenyl)- substituted chroman derivatives of structure 3 where in R1,R2, R3, R4 and R5 are as stated above and R6 is a methyl iodide salt of a substituted amino alkoxy group, with an inorganic base selected from NaOH, KOH, AgOH, Hg (OH) 2 and the like, isolating the hydroxide salt and reacting the isolated hydroxide salt with cyclic amines selected from 1, 4-Diazabicyclo[2.2.2] octane (DABCO) , DBU in a high boiling solvent such as diethylene glycol, ethylene glycol or similar solvents at a temperature in the range of 80°C to 200°C for a period of 5 minutes to 8 hrs or insitu conversion of methyliodide salt to desired compound of structure 2 using above stated methodology. (Figure Removed) In an embodiment of the invention wherein R1 is 7-OMe, R2 and R3 are CH3, R4 and R5 are H atoms, In an embodiment of the invention wherein R1 is 7-OMe, R2 and R3 are H, R4 and R5 are H atoms. In yet another embodiment of the invention wherein the inorganic base may be selected from NaOH, KOH, AgOH, Hg (OH) 2 and the like NaOH, preferably NaOH In still another embodiment of the invention where in the cyclic amine used is selected from 1,4-Diazabicyclo[2.2.2] octane (DABCO), DBU preferably DABC. In further embodiment of the invention wherein the high boiling solvent used may be selected from diethylene glycol, ethylene glycol or similar solvents. Instill further embodiment of the invention where in the solvent used with DABCO is preferably ethylene glycol. In further embodiment of the invention where in the reaction temperature may be ranging between 80-120°C. Instill further embodiment of the invention wherein the preferred process of preparation of compounds of claim 1 where in hydroxide salt generated in situ is treated withjhe cyclic amine under condition mentioned in claim 1 in a one pot reaction. Disclosure of the invention: The present invention concerns (-) 3R, 4R - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans of the structure 2, accompanying this specification where in R\ and Rt are individually hydrogen, hydroxy, halogens, C^ alkyl, d.6 alkoxy, R2, R3, are individually hydrogen, Ci-6 alkyl and Rs is (Figure Remove) hydrogen, halogen, nitro, cyano, Ci.6 alkyl or c , alkyloxy, a perse known process of preparation for the same by treating 3R, 4R- trans - 2,2-dialkyl -3- substituted phenyl-4- (co-aminoalkoxy substituted phenyl)- substituted chroman derivatives of structure 3 of the Scheme 1 accompanying this specification where in RI, R2, RS, R4 and RS are as stated above and Re is a methyl iodide salt of a substituted amino alkoxy group, with an inorganic base such as NaOH, KOH, AgOH, Hg (OH) 2 and the like, and subsequent reaction of the isolated hydroxide salt with cyclic amines such as 1, 4-Diazabicyclo[2.2.2] octane (DABCO) in a high boiling solvent such as diethylene glycol, ethylene glycol or similar solvents at a temperature in the range of 80°C to 200°C for a period of 5 mins to 8 hrs or insitu conversion of methyliodide salt to desired compound of structure 1 using above stated methodology. The following examples are given by way of illustration and should not construed the scope of the invention . Example 1: 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman (1: Rt = 7-OMe, R2 = R3 = Me, R4 = R5 = H, X = H): 3R, 4R (-) - trans - 2,2-dialkyl -3- substituted phenyl-4- (4-p-pyrrolidinoethoxy phenyl)- 7-methoxy chromans di-p-toluoyl tartaric acid salt (6.6 gm) (1: RI = 7-OMe, Ra = RS = Me, R4 = RS H, X = di-p-toluoyl tartrate) was suspended in a mixture of toluene (30 ml) water (30 ml) and sodium hydroxide (3 gm). The mixture was stirred until all the salts have dissolved and stirring continued for further 2 hrs. The aqueous phase was separated and extracted with toluene (20 ml) and washed with water and dried by azeotropic distillation to give an oil. The structure of title compound was verified by H NMR and elemental analysis. Yield (79%), [a]D = -177 (methanol) OR Example 2: 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman (1: RI = 7-OMe, R2 = R3 = Me, R4 = R5 = H, X = H): 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman)- di-p-toluoyl tartaric acid (10 gm) was dissolved in 50 ml liquor ammonia the reaction was stirred at room temperature for 1 hr till all the solid dissolved and reaction mixture was extracted with 120 ml of dichloromethane. Organic laver was seperated and washed with water and dried on sodium sulfate and concentrated to give free base as an oil. The structure of the title compound was verified by 'H NMR and elemental analysis. Yield (80%), [a]D = -177 (methanol) OR Example 3: 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-?- raethoxychroman (1: RI = 7-OMe, R2 = R3 = Me, IL, - R5 = H, X = H): 3R, 4R (-) - trans - 2,2-dialkyl -3- substituted phenyl-4- (4-(3-pyrrolidinoethoxy phenyl)- 7-methoxy chromans fumerate (10 gm) (1: RI = 7-OMe, Ra = RS = Me, R4 = RS H, X = fumerate) was suspended in a mixture of toluene (40 ml), water (40 ml) and sodium hydroxide (3.5 gm). The mixture was stirred until all the salts have dissolved and stirring continued for further 2 hrs. The aqueous phase was separated and extracted with toluene (25 ml) and washed with water and dried by azeotropic distillation to give an oil. The structure of the title compound was verified by LH NMR and elemental analysis. Yield (80%), = -177 (methanol) OR Example 4: 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-?-methoxychroraan (1: RI = 7-OMe, R2 = RS = Me, R4 = R5 = H, X = H): 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman)- fumerate (10 gm) was dissolved in 40 ml liquor ammonia the reaction was stirred at room temperature for 1 hr till all the solid dissolved and reaction mixture was extracted with 120 ml of dichloromethane. Organic layer was separated and washed with water and dried on sodium sulfate and concentrated to give free base as an oil. The structure of the title compound was verified by 1H NMR and elemental analysis. Yield (78%), [x]D = -177 (methanol) Example 5: 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-?-methoxychroman, methyl iodide (3: RI = 7-OMe, RI = RS = Me, R = R5 = H, R& = P-pyrrolidinoethoxy, methyl iodide salt): 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman (9.5 gm) was dissolved in acetone (400 ml) and K2CO3 (30 gm) was added to the reaction mixture. Methyl iodide (12 ml) was added to above mixture, which was refluxed for 4 hrs. The K^COs was filtered off and acetone was concentrated. Reaction mixture was diluted with 60 ml ethylacetate and washed with water several times. The organic layer was then evaporated to yield methyl iodide salt. The structure of the title compound was verified by *H NMR and elemental analysis. Yield (81%), [a]D = -132 (methanol), m.p. 200-202. Example 6: 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl iodide (3: RI = 7-OMe, R2 = R3 = Me, R4 = R5 = H, R6 = (3-pyrrolidinoethoxy, methyl iodide salt): 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-?-methoxychroman, (lOg) and methyl iodide (12 ml) were heated in steel bomb or hi sealed tube for 4 hrs which on extraction with ethylacetate give methyl iodide salt. The structure of the title compound was verified by 'H NMR and elemental analysis. Yield (80%), = -132 (methanol), m.p. 200-202. OR Example 7: 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-hydroxyphenyl)-7-methoxychroman (2: R, = 7-OMe, R2 = R3 = Me, R4 = H): A mixture of 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-(}-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl iodide salt (11.6 gm) and NaOH (8 gm) in ethylene glycol (150 ml) was heated to 130°C for 1 hr; DABCO (2.6 gm) was added to reaction mixture and heating was continued further for 1 hrs. It was diluted with water and extracted with ethyl acetate. The organic layer was then washed with water and dried over sodium sulfate and concentrated to give the title compound. Yield (83%), [a]D = - 215 (methanol), m.p. 260-262°C. We Claim: 1 A process for the preparation of (-) 3R, 4R - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans of the structure 2, where in R1 and R4 are individually hydrogen, hydroxy, halogens, C1-6 alkyl, C1-6 alkoxy, R2, R3, are individually hydrogen, C1-6 alkyl and R5 is hydrogen, halogen, nitro, cyano, C1-6 alkyl or cyclic alkyloxy, treating 3R, 4R- trans - 2,2-dialkyl -3- substituted phenyl-4-(ω-aminoalkoxy substituted phenyl)- substituted chroman derivatives of structure 3 where in R1 R2j R3, R4 and R5 are as stated above and R6 is a methyl iodide salt of a substituted amino alkoxy group, with an inorganic base selected from NaOH, KOH, AgOH, Hg (OH) 2 and the like, isolating the hydroxide salt and reacting the isolated hydroxide salt with cyclic amines selected from 1, 4-Diazabicyclo[2.2.2] octane (DABCO) , DBU in a high boiling solvent such as diethylene glycol, ethylene glycol or similar solvents at a temperature in the range of 80°C to 200°C for a period of 5 minutes to 8 hrs or insitu conversion of methyliodide salt to desired compound of structure 2 using above stated methodology. (Formula Removed) 2 A process as claimed in claim 1 wherein R1 is 7-OMe, R2 and R3 are CH3, R4 and R5 are H atoms, 3 A process as claimed in claim 1 wherein R1 is 7-OMe, R2 and R3 are H, R4 and R5 are H atoms. 4 A process as claimed in claim 11 wherein the preferable inorganic base is NaOH. 5 A process as claimed in claim 1 where the preferable cyclic amine used in DABCO. 6 A process as claimed in claim 1 where in the preferable solvent is ethylene glycol. 7 A process as claimed in claim 1 where in the reaction temperature is 80-120°C. 8 A process for the preparation of (-) 3R, 4R - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans substantially as herein described with reference to the examples and drawings accompanying the specification.

Full Text

Field of the Invention
This invention relates to a process for the preparation of (-) 3R, 4R - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans. The product is used as key intermediates for the preparation of tissue selective estrogens as pharmaceuticals.
The main objective of the present invention is to provide a process for the preparation of 3R, 4R (-) - trans - 2,2-dialkyl -3- substituted phenyl-4-(hydroxy substituted phenyl)- substituted chromans, key intermediate for the synthesis of compounds having significant medicinal properties such as contraceptives, fertility inducers, breast cancer, osteoporosis, hyper cholesteremia, estrogen replacement therapy, anti-inflammatory ,prostatic carcinoma CNS and CVS disorders.
Trans - 2,2-alkyl -3- phenyl-4-(4(2-tertiary aminoethoxy phenyl)-7-methoxy chroman shown below wherein R1 and R2 are individually H or lower alkyl ,R3 and R4 are lower alkyl or forms a nitrogen heterocycle including the nitrogen atom eg. pyrrolidine or piperidine etc. (n = 1 to 4) have been found useful as contraceptives.
(Figure Removed)
Figure I
Suprabhat Ray, Amita Tandon, Indra Dwivedy,
Scott R. Wilson, James P. O'Neil , and John A. Katzenellenbogen (1994). An
X-ray crystallographic study of the non-steroidal contraceptive agents
Centchroman J. Med. Chem., 37, 696-700; V. P. Kamboj, A. B. Kar, S. Ray , P.K. Grover and Nitya Anand(1971). Antifertility activity of 3, 4-trans 2,2-dimethyl-3-phenyl-4-p-(ß-pyrrolidinoethoxy phenyl-7-methoxychroman, Ind. J. Exp.

Biol. 9, 103. S. Ray, P.K. Grover and Nitya Anand (1971). A new synthesis of cis and trans 3-phenyl-4-(4-p-pyrrolidinocthoxy) phenyl-7-methoxy chroman, Ind. J. Chem. 9, 727. S. Ray, P.K. Grover, V.P. Kamboj, B.S. Setty, Amiya B, Kar, and Nitya Anand, (1976) Studies in Antifertility agents: Part XII- Structure activity relationship study of 3, 4-diphenyl chromenes and chromans, J. Med. Chem. 19,276.
Resolution of free base of 1 wherein RI = 7-OMe; R2= Me; R3= Me, R4 and R5 = H and X = H, led to the 3R,4R (-) and 3S, 4S (+) enantiomers of 1, optionally converted into its salt of 1 wherein RI, R2, RS, R4 and RS are as defined above and X is an anion of an acid such as HC1, fumaric acid, tartaric acid etc.
(Figure Remove) M. Salman, S. Ray, N Anand,. A. K. Agarwal, M. M. Singh, B.S. Setty, V.P. Kamboj (1986), Studies in antifertility agents 50: stereoselective binding of d- and 1-centchromans to estrogen receptor and their antifertility activity, J. Med. Chem. 29: 1801-1803. Back ground of the invention:
Estrogen agonists as well as antagonists elicit biological activity through their binding to estrogen receptor. In case of a chiral ligand, a specific chirality favours receptor binding. Thus, d-estradiol shows many fold higher affinity towards estrogen receptor binding as compared to 1-estradiol. In the case of trans-3,4-diaryl chromans of structure 1, 3R, 4R- trans- chroman wherein RI= 7-OMe; R2=Me; R3=Me, R» and R5 = H shows 7 fold higher affinity for ER binding as compared to the 3R, 4R- form and also elicits similar order of anti-implantation activity (JMC.29, 1801-1803). It is also possible that the different enantiomers may show different biological activities and also
pharmacokinetic properties. Therefore, use of single enantiomeric forms as
pharmaceutical is recommended.
In order to develop enantiomers of trans-3,4-diaryl chromans Figure I substituted with various amino alkoxy side chain, which is known to play a major role in deciding their antiestrogenic activities and towards development of selective estrogen receptor modulators (SERM), it was therefore, necessary to synthesize hydroxy derivatives of (3R, 4R) and (3S, 4S) enantiomers of trans-3, 4-diaryl chromans 2 which would serve as intermediate for the preparation of aminoalkoxy side chain substituted final products.
The object of the present investigation was therefore to develop a process for the preparation of trans-3R, 4R 3-aryl-4-(hydroxyphenyl)- substituted chromans 2, which would serve as the key intermediate for the preparation of 3R, 4R- trans-3,4-diaryl substituted chromans variously substituted with substituted amino alkyl groups on the 4-phenyl residue.
Accordingly, the present invention relates to a process for the preparation of (-) 3R, 4R - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)-substituted chromans of the structure 2, where in R1 and R4 are individually hydrogen, hydroxy, halogens, C1-6 alkyl, C1-6 alkoxy, R2, R3, are individually hydrogen, C1-6 alkyl and R5 is hydrogen, halogen, nitro, cyano, C1-6 alkyl or cyclic alkyloxy, treating 3R, 4R- trans - 2,2-dialkyl -3- substituted phenyl-4-(ω-aminoalkoxy substituted phenyl)- substituted chroman derivatives of structure 3 where in R1,R2, R3, R4 and R5 are as stated above and R6 is a methyl iodide salt of a substituted amino alkoxy group, with an inorganic base selected from NaOH, KOH, AgOH, Hg (OH) 2 and the like, isolating the hydroxide salt and reacting the isolated hydroxide salt with cyclic amines selected from 1, 4-Diazabicyclo[2.2.2] octane (DABCO) , DBU in a high boiling solvent such as diethylene glycol, ethylene glycol or similar solvents at a temperature in the range of 80°C to 200°C for a period of 5 minutes to 8 hrs or insitu conversion of methyliodide salt to desired compound of structure 2 using above stated methodology.
(Figure Removed)
In an embodiment of the invention wherein R1 is 7-OMe, R2 and R3 are CH3, R4 and R5 are H atoms,
In an embodiment of the invention wherein R1 is 7-OMe, R2 and R3 are H, R4 and R5 are H atoms.

In yet another embodiment of the invention wherein the inorganic base may be selected
from NaOH, KOH, AgOH, Hg (OH) 2 and the like NaOH, preferably NaOH
In still another embodiment of the invention where in the cyclic amine used is selected
from 1,4-Diazabicyclo[2.2.2] octane (DABCO), DBU preferably DABC.
In further embodiment of the invention wherein the high boiling solvent used may be
selected from diethylene glycol, ethylene glycol or similar solvents.
Instill further embodiment of the invention where in the solvent used with DABCO is
preferably ethylene glycol.
In further embodiment of the invention where in the reaction temperature may be
ranging between 80-120°C.
Instill further embodiment of the invention wherein the preferred process of preparation of compounds of claim 1 where in hydroxide salt generated in situ is treated withjhe cyclic amine under condition mentioned in claim 1 in a one pot reaction.
Disclosure of the invention:

The present invention concerns (-) 3R, 4R - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans of the structure 2, accompanying this specification where in R\ and Rt are individually hydrogen, hydroxy, halogens, C^ alkyl, d.6 alkoxy, R2, R3, are individually hydrogen, Ci-6 alkyl and Rs is
(Figure Remove) hydrogen, halogen, nitro, cyano, Ci.6 alkyl or c , alkyloxy, a perse known process of preparation for the same by treating 3R, 4R- trans - 2,2-dialkyl -3- substituted phenyl-4-
(co-aminoalkoxy substituted phenyl)- substituted chroman derivatives of structure 3 of the Scheme 1 accompanying this specification where in RI, R2, RS, R4 and RS are as stated above and Re is a methyl iodide salt of a substituted amino alkoxy group, with an inorganic base such as NaOH, KOH, AgOH, Hg (OH) 2 and the like, and subsequent reaction of the isolated hydroxide salt with cyclic amines such as 1, 4-Diazabicyclo[2.2.2] octane (DABCO) in a high boiling solvent such as diethylene glycol, ethylene glycol or similar solvents at a temperature in the range of 80°C to 200°C for a period of 5 mins to 8 hrs or insitu conversion of methyliodide salt to desired compound of structure 1 using above stated methodology.
The following examples are given by way of illustration and should not construed the scope of the invention . Example 1:
3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman (1: Rt = 7-OMe, R2 = R3 = Me, R4 = R5 = H, X = H):
3R, 4R (-) - trans - 2,2-dialkyl -3- substituted phenyl-4- (4-p-pyrrolidinoethoxy phenyl)- 7-methoxy chromans di-p-toluoyl tartaric acid salt (6.6 gm) (1: RI = 7-OMe, Ra = RS = Me, R4 = RS H, X = di-p-toluoyl tartrate) was suspended in a mixture of toluene (30 ml) water (30 ml) and sodium hydroxide (3 gm). The mixture was stirred until all the salts have dissolved and stirring continued for further 2 hrs. The aqueous phase was separated and extracted with toluene (20 ml) and washed with water and dried by azeotropic distillation to give an oil. The structure of title compound was verified by *H NMR and elemental analysis. Yield (79%), [a]D = -177 (methanol) OR
Example 2:
3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman (1: RI = 7-OMe, R2 = R3 = Me, R4 = R5 = H, X = H):
3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman)- di-p-toluoyl tartaric acid (10 gm) was dissolved in 50 ml liquor ammonia the reaction was stirred at room temperature for 1 hr till all the solid dissolved and reaction mixture was extracted with 120 ml of dichloromethane. Organic laver was seperated and washed with water and dried on sodium sulfate and concentrated to give
free base as an oil. The structure of the title compound was verified by 'H NMR and
elemental analysis. Yield (80%), [a]D = -177 (methanol)
OR
Example 3:
3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-?-
raethoxychroman (1: RI = 7-OMe, R2 = R3 = Me, IL, - R5 = H, X = H):
3R, 4R (-) - trans - 2,2-dialkyl -3- substituted phenyl-4- (4-(3-pyrrolidinoethoxy phenyl)- 7-methoxy chromans fumerate (10 gm) (1: RI = 7-OMe, Ra = RS = Me, R4 = RS H, X = fumerate) was suspended in a mixture of toluene (40 ml), water (40 ml) and sodium hydroxide (3.5 gm). The mixture was stirred until all the salts have dissolved and stirring continued for further 2 hrs. The aqueous phase was separated and extracted with toluene (25 ml) and washed with water and dried by azeotropic distillation to give an oil. The structure of the title compound was verified by LH NMR and elemental analysis. Yield (80%), = -177 (methanol) OR
Example 4:
3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-?-methoxychroraan (1: RI = 7-OMe, R2 = RS = Me, R4 = R5 = H, X = H):
3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman)- fumerate (10 gm) was dissolved in 40 ml liquor ammonia the reaction was stirred at room temperature for 1 hr till all the solid dissolved and reaction mixture was extracted with 120 ml of dichloromethane. Organic layer was separated and washed with water and dried on sodium sulfate and concentrated to give free base as an oil. The structure of the title compound was verified by 1H NMR and elemental analysis. Yield (78%), [x]D = -177 (methanol) Example 5:
3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-?-methoxychroman, methyl iodide (3: RI = 7-OMe, RI = RS = Me, R* = R5 = H, R& = P-pyrrolidinoethoxy, methyl iodide salt):
3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman (9.5 gm) was dissolved in acetone (400 ml) and K2CO3 (30 gm) was added to the reaction mixture. Methyl iodide (12 ml) was added to above mixture, which was refluxed for 4 hrs. The K^COs was filtered off and acetone was concentrated. Reaction mixture was diluted with 60 ml ethylacetate and washed with water several times. The organic layer was then evaporated to yield methyl iodide salt. The structure of the title compound was verified by *H NMR and elemental analysis. Yield (81%), [a]D = -132 (methanol), m.p. 200-202. Example 6:
3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl iodide (3: RI = 7-OMe, R2 = R3 = Me, R4 = R5 = H, R6 = (3-pyrrolidinoethoxy, methyl iodide salt):
3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-?-methoxychroman, (lOg) and methyl iodide (12 ml) were heated in steel bomb or hi sealed tube for 4 hrs which on extraction with ethylacetate give methyl iodide salt. The structure of the title compound was verified by 'H NMR and elemental analysis. Yield (80%), = -132 (methanol), m.p. 200-202. OR
Example 7:
3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-hydroxyphenyl)-7-methoxychroman (2: R, = 7-OMe, R2 = R3 = Me, R4 = H):
A mixture of 3R, 4R (-) - trans - 2,2-dimethyl -3-phenyl-4-(4-(}-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl iodide salt (11.6 gm) and NaOH (8 gm) in ethylene glycol (150 ml) was heated to 130°C for 1 hr; DABCO (2.6 gm) was added to reaction mixture and heating was continued further for 1 hrs. It was diluted with water and extracted with ethyl acetate. The organic layer was then washed with water and dried over sodium sulfate and concentrated to give the title compound. Yield (83%), [a]D = - 215 (methanol), m.p. 260-262°C.

We Claim:
1 A process for the preparation of (-) 3R, 4R - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans of the structure 2, where in R1 and R4 are individually hydrogen, hydroxy, halogens, C1-6 alkyl, C1-6 alkoxy, R2, R3, are individually hydrogen, C1-6 alkyl and R5 is hydrogen, halogen, nitro, cyano, C1-6 alkyl or cyclic alkyloxy, treating 3R, 4R- trans - 2,2-dialkyl -3- substituted phenyl-4-(ω-aminoalkoxy substituted phenyl)- substituted chroman derivatives of structure 3 where in R1 R2j R3, R4 and R5 are as stated above and R6 is a methyl iodide salt of a substituted amino alkoxy group, with an inorganic base selected from NaOH, KOH, AgOH, Hg (OH) 2 and the like, isolating the hydroxide salt and reacting the isolated hydroxide salt with cyclic amines selected from 1, 4-Diazabicyclo[2.2.2] octane (DABCO) , DBU in a high boiling solvent such as diethylene glycol, ethylene glycol or similar solvents at a temperature in the range of 80°C to 200°C for a period of 5 minutes to 8 hrs or insitu conversion of methyliodide salt to desired compound of structure 2 using above stated methodology.
(Formula Removed)
2 A process as claimed in claim 1 wherein R1 is 7-OMe, R2 and R3 are CH3, R4 and R5 are H atoms,
3 A process as claimed in claim 1 wherein R1 is 7-OMe, R2 and R3 are H, R4 and R5 are H atoms.

4 A process as claimed in claim 11 wherein the preferable inorganic base is NaOH.
5 A process as claimed in claim 1 where the preferable cyclic amine used in DABCO.
6 A process as claimed in claim 1 where in the preferable solvent is ethylene glycol.
7 A process as claimed in claim 1 where in the reaction temperature is 80-120°C.
8 A process for the preparation of (-) 3R, 4R - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans substantially as herein described with reference to the examples and drawings accompanying the specification.

Documents:

305-DEL-2003-Abstract-(04-09-2008).pdf

305-del-2003-abstract.pdf

305-DEL-2003-Claims-(04-09-2008).pdf

305-del-2003-claims.pdf

305-DEL-2003-Correspondence-Others-(04-09-2008).pdf

305-del-2003-correspondence-others.pdf

305-del-2003-correspondence-po.pdf

305-del-2003-description (complete)-04-09-2008.pdf

305-del-2003-description (complete).pdf

305-del-2003-drawings.pdf

305-del-2003-form-1.pdf

305-del-2003-form-18.pdf

305-DEL-2003-Form-2-(04-09-2008).pdf

305-del-2003-form-2.pdf

305-DEL-2003-Form-3-(04-09-2008).pdf

305-del-2003-form-3.pdf

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Patent Number

225322

Indian Patent Application Number

305/DEL/2003

PG Journal Number

48/2008

Publication Date

28-Nov-2008

Grant Date

07-Nov-2008

Date of Filing

17-Mar-2003

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	SANGITA	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P.)
2	ATUL KUMAR	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P.)
3	D.P. SAHU	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P.)
4	SUPRABHAT RAY	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226 001 (U.P.)

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