Title of Invention	A PROCESS FOR PREPARATION OF (+) 3S, 4S-TRANS-2, 2-DIALKYL-3- SUBSTITUTED PHENYL-4-(HYDROXY-SUBSTITUTED PHENYL)-SUBSTITUTED CHROMANS
Abstract	A process for preparation of (+) 3S,4S-trans - 2,2-dialkyl -3- substituted phenyl -4- (hydroxyl substituted phenyl)- substituted chromans from 3S.4S-trans - 2,2-dialkyl -3- substituted phenyl - 4-(aminoalkoxy substituted phenyl)-substituted chroman derivatives with an inorganic base, isolating the hydroxide salt reacting with cyclic amines in a high boiling solvent at a temperature in the range of 80°C to 200°C for a period ranging between 5 minutes to 8 hrs to provide the substituted chromane .

Title of Invention

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

Abstract

A process for preparation of (+) 3S,4S-trans - 2,2-dialkyl -3- substituted phenyl -4- (hydroxyl substituted phenyl)- substituted chromans from 3S.4S-trans - 2,2-dialkyl -3- substituted phenyl - 4-(aminoalkoxy substituted phenyl)-substituted chroman derivatives with an inorganic base, isolating the hydroxide salt reacting with cyclic amines in a high boiling solvent at a temperature in the range of 80°C to 200°C for a period ranging between 5 minutes to 8 hrs to provide the substituted chromane .

Full Text	Field of the Invention This invention relates to (+)- 3S, 4S -trans - 2,2-dialkyl -3- substituted phenyl-4-(hydroxy substituted phenyl)- substituted chromans, process for their preparation, 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 3S, 4S (+) - trans - 2,2-dialkyl -3- substituted phenyl-4-(hydroxy substituted phenyl)- substituted chromans, key intermediates 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 RI and R2 are individually H or lower alkyl ,Rs 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 Dwive r Scott R. Wilson, James P. O'Neil , •i 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-(p-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-(3-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 R\ = 7-OMe; R2= Me; Ra= 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, Ra, R4 and Rs are as defined above and X is an anion of an acid such as HC1, fumaric acid, tartaric acid etc. (Figure Removed) 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: 180J-1803. Background 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, Rt and RS = H shows 7 fold higher affinity for ER binding as compared to the 3S, 4S- 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-3S, 4S 3-aryl-4-(hydroxyphenyl)- substituted chromans 2, which would serve as the key intermediate for the preparation of 3S, 4S- trans-3,4-diaryl substituted chromans variously substituted with substituted amino alkyl groups on the 4-phenyl residue. The final compounds thus obtained show selective cholesterol lowering activity. Disclosure of the invention: The present invention concerns (+) 3S, 4S - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans of the structure 2. (Figure Removed) accompanying this specification where in Rj and R4 are individually hydrogen, hydroxy, halogens, C1-6 alkyl, C alkoxy, R2, RS, are individually hydrogen, Ci alkyl and RS is hydrogen, halogen, nitro, cyano, C\ alkyl or cyclic alkyloxy, a perse known process of preparation for the same by treating 3S, 4S- trans - 2,2-dialkyl -3-substituted phenyI-4-(w-aminoalkoxy substituted phenyl)- substituted chroman derivatives of structure 3 of the Scheme 1 accompanying this specification where in RI, Rj, Rs, R* and Rs are as stated above and Re is a methyl iodide salt of a substituted ammo 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 2 using above stated methodology. (Scheme Removed) Scheme 1 Accordingly the present invention provides a process for preparation of (+) 3S,4S-trans - 2,2-dialkyl -3- substituted phenyl -4- (hydroxyl substituted phenyl)- substituted chromans of the structure 2 of the drawings accompanying the specification, wherein 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, d-6 alkyl or cyclic alkyloxy, which comprises treating 3S, 4S -trans-2,2-dialkyl-3-substituted phenyl -4-(uj aminoalkoxy substituted phenyl)-substituted chroman derivatives of structure 3 of the drawing accompanying the specification 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, isolating the hydroxide salt of figure 3 of the drawings accompanying the specification wherein R1,R2, R3, R4 and R5 are as stated above and R6 is a methyl hydroxide salt of a substituted amino alkoxy group, 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 ranging 5 minutes to 8 hrs to obtain (+) 3S,4S-trans - 2,2-dialkyl -3- substituted phenyl -4- (hydroxyl substituted phenyl)-substituted chromans. In an embodiment of the present invention, wherein the compound of formula 2, R1 is 7-OMe, R2 and R3 are CH3, R4 and R5 is H atom. In yet another embodiment of the present invention the inorganic base may be selected from NaOH, KOH, AgOH, Hg (OH) 2, preferably NaOH. In still another embodiment of the present invention the cyclic amine used may be selected from DABCO, DBU and preferably DABCO. In a further embodiment of the present invention the high boiling solvent may be selected form diethylene glycol, ethylene glycol similar solvents. In yet another embodiment of the present invention the solvent used with DABCO is preferably ethylene glycol. In an another embodiment of the present invention the reaction temperature used may be ranging between 80° C-120°C. In a further embodiment of the present invention hydroxide salt generated in situ may be treated with the cyclic amine under condition mentioned in a one pot reaction. The following examples are given by way of illustrations and should not be construed to limit the scope of the invention . Example 1: 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyI-4-(4-f3-pyrroIidinoethoxy phenyl)-?- medioxychroman (1: R, = 7-OMe, R2 = R3 = Me, R4 = R5 - H, X = H): 3S, 4S (+•) - trans - 2,2-dialkyl -3- substituted phenyl-4- (4-0-pyrrolidinoethoxy phenyl)- 7-methoxy chromans di-p-toluoyl tartaric acid salt (6.6 gm) (1: Ri = 7-OMe, R2 = R3 = Me, R4 = R5 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 (85%), [a]D = + 170 (methanol) OR Example 2: 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrroIidinoethoxy phenyl)-?- methoxychroman (1. R, = 7-OMe, R2 = R3 = Me, R4 = R5 = H, X = H): 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman)- di-p-toluoyl tartaric acid (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 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%), [cc]D = + 170 (methanol). OR Example 3: 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-(3-pyrrolidinoethoxy phenyl)-?-methoxychroman (1: RI = 7-OMe, R2 = R3 = Me, R4 = R5 = H, X = H): 3S, 4S (+) - trans - 2,2-dialkyl -3- substituted phenyl-4- (4-P-pyrrolidinoethoxy phenyl)- 7-methoxy chromans fumerate (10 gm) (1: R\| = 7-OMe, RT = Ra = Me, R4 = RS H, X = fumerate) 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 (25 ml) and washed with water and dried by azeotropic distillation to give an oil. The structure of the title compound was verified by 'H NMR and elemental analysis. Yield (85%), [a]D = + 170 (methanol) OR Example 4: 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrroIidinoethoxy phenyl)-?-methoxychroman (1: R, = 7-OMe, R2 = R3 = Me, R4 = R5 = H, X - H): 3S, 4S (+) - 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 'H NMR and elemental analysis. Yield (75%), [oc]D = + 170 (methanol) Example 5: 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl iodide (3: RI = 7-OMe, R2 = Rs = Me, R4 = Rs = H, R$ = p-pyrrolidinoethoxy, methyl iodide salt): 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman (10 gm) was dissolved in acetone (400 ml) and K^COs (35 gm) was added to the reaction mixture. Methyl iodide (13 ml) was added to above mixture, which was refluxed for 4 hrs. The K.2CO3 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 = + 190 (methanol), m.p. 225-227. Example 6: 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyI)-7-methoxychroman, methyl iodide (3: RI = 7-OMe, R2 = Rs = Me, R» = R5 = H, Re = P-pyrrolidinoethoxy, methyl iodide salt): 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, (lOg) and methyl iodide (13 ml) were heated in steel bomb or in 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 (81%), [cc]D = + 190 (methanol), m.p. 225-227. Example 7: 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyI-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl hydroxide (3: RI = 7-OMe, R2 = RS = Me, R4 = Rs = H, R& = (3-pyrrolidinoethoxy, methyl hydroxide): 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl iodide salt (10 gm) was dissolved on absolute alcohol (70ml). To the reaction mixture NaOH (6 gm) was added and refluxed reaction for 4 hrs. On cooling hydroxide salt was separated out. The structure of the title compound was verified by !H NMR and elemental , t vsis. Yield (81%), [a]D = + 170 (methanol), m.p. 230-235. Example 8: 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-hydroxyphenyl)-7- methoxychroman (2: RI = 7-OMe, R2 = RS = Me, R4 = H): 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyi-4-(4-(3-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl hydroxide salt (5 gm) was dissolved in ethylene glycol (50ml) and 1.0 gm of DABCO was added. Reaction mixture was heated at 80°C for 1 hr. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate and concentrated to give the title compound. Yield (80%), [a]o = + 202 (methanol), m.p. 253-255°C. OR Example 9: 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-hydroxyphenyl)-7-methoxychroman (2: RI = 7-OMe, R2 = Rs = Me, R4 = H): A mixture of 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl iodide salt (11.86 gm) and NaOH (7.2 gm) in ethylene glycol (180 ml) was heated to 120°C for 1 hr; DABCO (2.4 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 (85%), [ We Claim 1. A process for preparation of (+) 3S,4S-trans - 2,2-dialkyl -3-substituted phenyl -4- (hydroxyl substituted phenyl)- substituted chromans ,wherein Rl and R4 are individually hydrogen, hydroxy, halogens, Cl-6 alkyl, C-i-6 alkoxy, R2, R3I are individually hydrogen, Cl-6 alkyl and R5 is hydrogen, halogen, nitro, cyano, Cl-6 alkyl or cyclic alkyloxy, which comprises treating 3S, 4S -trans-2,2-dialkyl-3-substituted phenyl -4-{w aminoalkoxy substituted phenyl)-substituted chroman derivatives of where in R'^ 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, isolating the hydroxide salt wherein Rl, R2, R3, R4 and R5 are as stated above and R6 is a methyl hydroxide salt of a substituted amino alkoxy group, 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 ranging 5 minutes to 8 hrs to obtain (+) 3S,4S-trans - 2,2-dialkyi -3-substituted phenyl -4- (hydroxyl substituted phenyl)-substituted chromans. 2. A process as claimed in claim 1 wherein the compound according to claim 1 wherein Rl is 7-OMe, R2 and R3 are CH3 , R4 and R5 are H atoms. 3. A process as claimed in claims 1 - 2 wherein compound according to claim 1 wherein Rl is 7-OMe, R2 and R3 are H, R4 and R5 are H atoms. 4. A process as claimed in claims 1-3 wherein the inorganic base is selected from NaOH, KOH, AgOH, Hg(0H)2, preferably NaOH. 5. A process as claimed in claims 1-4, wherein the cyclic amine used is selected from l,4,Diazabicyclo[2.2.2]octane, DiazabicycIo-undec-7-ene 6. A process as claimed in claims 1 - 5, wherein the high boiling solvent is selected from diethylene glycol, ethylene glycol. 7. A process as claimed in claims 1 to 6, wherein the solvent used with l,4,Diazabicyclo[2.2.2]octane is preferably ethylene glycol. 8. A process according to claims 1 to 7 wherein the reaction temperature used is ranging between 80°C to 120°C preferably. 9. A process for preparation of (+) 3S, 4S - trans - 2,2 - dialkyi -3-substituted phenyl -4- (hydroxyl substituted phenyl) - substituted chromans substantially as herein described with reference to examples 1 to 9

Full Text

Field of the Invention
This invention relates to (+)- 3S, 4S -trans - 2,2-dialkyl -3- substituted phenyl-4-(hydroxy substituted phenyl)- substituted chromans, process for their preparation, 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 3S, 4S (+) - trans - 2,2-dialkyl -3- substituted phenyl-4-(hydroxy substituted phenyl)- substituted chromans, key intermediates 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 RI and R2 are individually H or lower alkyl ,Rs 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 Dwive r Scott R. Wilson, James P. O'Neil ,
•i
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-(p-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-(3-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 R\ = 7-OMe; R2= Me; Ra= 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, Ra, R4 and Rs are as defined above and X is an anion of an acid such as HC1, fumaric acid, tartaric acid etc.
(Figure Removed)
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: 180J-1803.
Background 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, Rt and RS = H shows 7 fold higher affinity for ER binding as compared to the 3S, 4S- 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-3S, 4S 3-aryl-4-(hydroxyphenyl)- substituted chromans 2, which would serve as the key intermediate for the preparation of 3S, 4S- trans-3,4-diaryl substituted chromans variously substituted with substituted amino alkyl groups on the 4-phenyl residue.
The final compounds thus obtained show selective cholesterol lowering activity.

Disclosure of the invention:
The present invention concerns (+) 3S, 4S - trans - 2,2-dialkyl -3- substituted phenyl-4- (hydroxy substituted phenyl)- substituted chromans of the structure 2.
(Figure Removed)
accompanying this specification where in Rj and R4 are individually hydrogen, hydroxy, halogens, C1-6 alkyl, C alkoxy, R2, RS, are individually hydrogen, Ci alkyl and RS is hydrogen, halogen, nitro, cyano, C\ alkyl or cyclic alkyloxy, a perse known process of preparation for the same by treating 3S, 4S- trans - 2,2-dialkyl -3-substituted phenyI-4-(w-aminoalkoxy substituted phenyl)- substituted chroman derivatives of structure 3 of the Scheme 1 accompanying this specification where in RI, Rj, Rs, R* and Rs are as stated above and Re is a methyl iodide salt of a substituted ammo 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 2 using above stated methodology.
(Scheme Removed)
Scheme 1
Accordingly the present invention provides a process for preparation of (+) 3S,4S-trans - 2,2-dialkyl -3- substituted phenyl -4- (hydroxyl substituted phenyl)- substituted chromans of the structure 2 of the drawings accompanying the specification, wherein 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, d-6 alkyl or cyclic alkyloxy, which comprises treating 3S, 4S -trans-2,2-dialkyl-3-substituted phenyl -4-(uj aminoalkoxy substituted phenyl)-substituted chroman derivatives of structure 3 of the drawing accompanying the specification 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, isolating the hydroxide salt of figure 3 of the drawings accompanying the specification wherein R1,R2, R3, R4 and R5 are as stated above and R6 is a methyl hydroxide salt of a substituted amino alkoxy group, 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 ranging 5 minutes to 8 hrs to obtain (+) 3S,4S-trans - 2,2-dialkyl -3- substituted phenyl -4- (hydroxyl substituted phenyl)-substituted chromans.
In an embodiment of the present invention, wherein the compound of formula 2, R1 is 7-OMe, R2 and R3 are CH3, R4 and R5 is H atom.
In yet another embodiment of the present invention the inorganic base may be selected from NaOH, KOH, AgOH, Hg (OH) 2, preferably NaOH.
In still another embodiment of the present invention the cyclic amine used may be selected from DABCO, DBU and preferably DABCO.
In a further embodiment of the present invention the high boiling solvent may be selected form diethylene glycol, ethylene glycol similar solvents.
In yet another embodiment of the present invention the solvent used with DABCO is preferably ethylene glycol.
In an another embodiment of the present invention the reaction temperature used may be ranging between 80° C-120°C.
In a further embodiment of the present invention hydroxide salt generated in situ may be treated with the cyclic amine under condition mentioned in a one pot reaction. The following examples are given by way of illustrations and should not be construed to limit the scope of the invention .
Example 1:
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyI-4-(4-f3-pyrroIidinoethoxy phenyl)-?-
medioxychroman (1: R, = 7-OMe, R2 = R3 = Me, R4 = R5 - H, X = H):
3S, 4S (+•) - trans - 2,2-dialkyl -3- substituted phenyl-4- (4-0-pyrrolidinoethoxy phenyl)- 7-methoxy chromans di-p-toluoyl tartaric acid salt (6.6 gm) (1: Ri = 7-OMe, R2 = R3 = Me, R4 = R5 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 (85%), [a]D = + 170 (methanol) OR
Example 2:
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrroIidinoethoxy phenyl)-?-
methoxychroman (1. R, = 7-OMe, R2 = R3 = Me, R4 = R5 = H, X = H):
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman)- di-p-toluoyl tartaric acid (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 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%), [cc]D = + 170 (methanol). OR
Example 3:
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-(3-pyrrolidinoethoxy phenyl)-?-methoxychroman (1: RI = 7-OMe, R2 = R3 = Me, R4 = R5 = H, X = H):
3S, 4S (+) - trans - 2,2-dialkyl -3- substituted phenyl-4- (4-P-pyrrolidinoethoxy phenyl)- 7-methoxy chromans fumerate (10 gm) (1: R| = 7-OMe, RT = Ra = Me, R4 = RS H, X = fumerate) 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 (25 ml) and washed with water and dried by azeotropic distillation to give an oil. The structure of the title compound was verified by 'H NMR and elemental analysis. Yield (85%), [a]D = + 170 (methanol) OR
Example 4:
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrroIidinoethoxy phenyl)-?-methoxychroman (1: R, = 7-OMe, R2 = R3 = Me, R4 = R5 = H, X - H):
3S, 4S (+) - 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 'H NMR and elemental analysis. Yield (75%), [oc]D = + 170 (methanol) Example 5:
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl iodide (3: RI = 7-OMe, R2 = Rs = Me, R4 = Rs = H, R$ = p-pyrrolidinoethoxy, methyl iodide salt):
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman (10 gm) was dissolved in acetone (400 ml) and K^COs (35 gm)
was added to the reaction mixture. Methyl iodide (13 ml) was added to above mixture, which was refluxed for 4 hrs. The K.2CO3 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 = + 190 (methanol), m.p. 225-227. Example 6:
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyI)-7-methoxychroman, methyl iodide (3: RI = 7-OMe, R2 = Rs = Me, R» = R5 = H, Re = P-pyrrolidinoethoxy, methyl iodide salt):
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, (lOg) and methyl iodide (13 ml) were heated in steel bomb or in 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 (81%), [cc]D = + 190 (methanol), m.p. 225-227. Example 7:
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyI-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl hydroxide (3: RI = 7-OMe, R2 = RS = Me, R4 = Rs = H, R& = (3-pyrrolidinoethoxy, methyl hydroxide):
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl iodide salt (10 gm) was dissolved on absolute alcohol (70ml). To the reaction mixture NaOH (6 gm) was added and refluxed reaction for 4 hrs. On cooling hydroxide salt was separated out. The structure of the title compound was verified by !H NMR and elemental , t vsis. Yield (81%), [a]D = + 170 (methanol), m.p. 230-235.
Example 8:
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-hydroxyphenyl)-7-
methoxychroman (2: RI = 7-OMe, R2 = RS = Me, R4 = H):
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyi-4-(4-(3-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl hydroxide salt (5 gm) was dissolved in ethylene glycol (50ml) and 1.0 gm of DABCO was added. Reaction mixture was heated at 80°C for 1 hr. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate and concentrated to give the title compound. Yield (80%), [a]o = + 202 (methanol), m.p. 253-255°C. OR
Example 9:
3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-hydroxyphenyl)-7-methoxychroman (2: RI = 7-OMe, R2 = Rs = Me, R4 = H):
A mixture of 3S, 4S (+) - trans - 2,2-dimethyl -3-phenyl-4-(4-p-pyrrolidinoethoxy phenyl)-7-methoxychroman, methyl iodide salt (11.86 gm) and NaOH (7.2 gm) in ethylene glycol (180 ml) was heated to 120°C for 1 hr; DABCO (2.4 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 (85%), [

We Claim
1. A process for preparation of (+) 3S,4S-trans - 2,2-dialkyl -3-substituted phenyl -4- (hydroxyl
substituted phenyl)- substituted chromans ,wherein Rl and R4 are individually hydrogen, hydroxy, halogens, Cl-6 alkyl, C-i-6 alkoxy, R2, R3I are individually hydrogen, Cl-6 alkyl and R5 is hydrogen, halogen, nitro, cyano, Cl-6 alkyl or cyclic alkyloxy, which comprises treating 3S, 4S -trans-2,2-dialkyl-3-substituted phenyl -4-{w aminoalkoxy substituted phenyl)-substituted chroman derivatives of where in R'^ 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, isolating the hydroxide salt wherein Rl, R2, R3, R4 and R5 are as stated above and R6 is a methyl hydroxide salt of a substituted amino alkoxy group, 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 ranging 5 minutes to 8 hrs to obtain (+) 3S,4S-trans - 2,2-dialkyi -3-substituted phenyl -4- (hydroxyl substituted phenyl)-substituted chromans.
2. A process as claimed in claim 1 wherein the compound according to claim 1 wherein Rl is 7-OMe, R2 and R3 are CH3 , R4 and R5 are H atoms.
3. A process as claimed in claims 1 - 2 wherein compound according to claim 1 wherein Rl is 7-OMe, R2 and R3 are H, R4 and R5 are H atoms.

4. A process as claimed in claims 1-3 wherein the inorganic base is selected from NaOH, KOH, AgOH, Hg(0H)2, preferably NaOH.
5. A process as claimed in claims 1-4, wherein the cyclic amine used is selected from l,4,Diazabicyclo[2.2.2]octane, DiazabicycIo-undec-7-ene
6. A process as claimed in claims 1 - 5, wherein the high boiling solvent is selected from diethylene glycol, ethylene glycol.
7. A process as claimed in claims 1 to 6, wherein the solvent used with l,4,Diazabicyclo[2.2.2]octane is preferably ethylene glycol.
8. A process according to claims 1 to 7 wherein the reaction temperature used is ranging between 80°C to 120°C preferably.

9. A process for preparation of (+) 3S, 4S - trans - 2,2 - dialkyi -3-substituted phenyl -4-
(hydroxyl substituted phenyl) - substituted chromans substantially as herein described with reference to examples 1 to 9

Documents:

260-DEL-2003-Abstract-(19-09-2008).pdf

260-del-2003-abstract.pdf

260-DEL-2003-Claims-(19-09-2008).pdf

260-del-2003-claims-(30-03-2009).pdf

260-del-2003-claims.pdf

260-del-2003-complete specification (granted).pdf

260-DEL-2003-Correspondence-Others-(19-09-2008).pdf

260-del-2003-correspondence-others.pdf

260-del-2003-correspondence-po.pdf

260-DEL-2003-Description (Complete)-(19-09-2008).pdf

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

260-del-2003-drawings.pdf

260-del-2003-form-1.pdf

260-del-2003-form-18.pdf

260-DEL-2003-Form-2-(19-09-2008).pdf

260-del-2003-form-2.pdf

260-del-2003-form-3.pdf

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Patent Number

233470

Indian Patent Application Number

260/DEL/2003

PG Journal Number

14/2009

Publication Date

27-Mar-2009

Grant Date

30-Mar-2009

Date of Filing

10-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 PLACE, LUCKNOW-226 001, (U.P)INDIA.
2	ATUL KUMAR	CENTRAL DRUG RESEARCH INSTITUTE CHATTAR MANZIL PLACE, LUCKNOW-226 001, (U.P)INDIA.
3	SUPRABHAT RAY	CENTRAL DRUG RESEARCH INSTITUTE CHATTAR MANZIL PLACE, LUCKNOW-226 001, (U.P)INDIA.

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA