Title of Invention

2,3-DIPHENYL (SUBSTITUTED)- -4-(TERT-BUTYLDIMETHYLSILYLOXY) CYCLOPENT-2-EN-1-ONE

Abstract

This invention relates to 2,3-diphenyl(substituted)-4-(tert-butyldimethylsilyloxy)-cyclopent-2-en-1-ones of the formula 1, wherein R1 to R9 are each independently selected from the group consisting of hydrogen, azido, halo, carboxymethyl, methoxy, methyl and nitro; X is =O or NOH. The compound and their derivatives shows cytotoxic activity against various cancer lines and exhibits promising activity.

Full Text

The present invention relates to 2,3-diphenyl(substituted)-diaryl-4-(tert-butyldimethylsilyloxy)-cyclopent-2-en-l-one of the formula (1). (Formula Removed) More particularly it relates to a 2,3-diphenyl (substituted)-4--(tert-butyldimethylsilyloxy)-cyclopent-2-en-l-one of the formula (1) wherein R1 to R9 are each independently hydrogen, azido, halo, carboxymethyl, methoxy, methyl, nitro; X is =O or =NOH prepared from the corresponding 2-aryl(substituted)-4-(tert-butyldimethylsilyloxy)-cyclopent-2-en-l -one having formula (2) wherein R1 to R5 are each independently hydrogen, azido, halo, methoxy, methyl, nitro and X is =O. (Formula Removed) Some of the 2,3-diphenyl(substituted)-4--(tert-butyldimethylsilyloxy)-cyclopent-2-en-l-ones of the formula (1) and their derivatives e.g. oximes when X = NOH, acetates have shown cytotoxic activity against various cancer cell lines and were found to exhibit promising activity. The lead molecule thus derived from these biological studies is under Quantitative Structure Activity Relationship studies in our laboratory. The synthesis of novel 2,3-diphenyl(substituted)-4--(tert-butyldimethylsilyloxy)-cyclopent-2-en-1-ones of the formula (1) wherein R1 to R9 are each independently selected from the group consisting of hydrogen, azido, halo, carboxymethyl, methoxy, methyl and nitro; X is =0 or =NOH is reported herein for the first time and no prior art is available in respect of process for the preparation of these molecules. The compounds of the formula (1) wherein R1 to R9 are each independently selected from the group consisting of hydrogen, azido, halo, carboxymethyl, methoxy, methyl and nitro; X is =0 or =NOH. have been prepared by employing Heck reaction on 2-aryl(substituted)-4-(tert-butyldimethylsilyloxy)-cyclopent-2-en-1 -one. The compound 2-aryl (substituted)-4-(tert-butyldimethylsilyloxy)-cyclopent-2-en-l-one of formula (2) ) wherein R1 to R9 are each independently selected from the group consisting of hydrogen, azido, halo, carboxymethyl, methoxy, methyl and nitro; X is =O is prepared by a procedure as disclosed and claimed in our co-pending Indian patent application no. 0790del2002. The present invention therefore provides for the preparation of 2,3-diphenyl (substituted)-4-(tert-butyldimethylsilyloxy)-cyclopent-2-en-l-ones of the formula (1) wherein R1 to R9 are each independently selected from the group consisting of hydrogen, azido, halo, carboxymethyl, methoxy, methyl and nitro; X is =0 or =NOH from the corresponding 2-aryl (substituted)-4-(tert-butyldimethylsilyloxy) -cyclopent-2-en-l-one wherein R1 to R5 are each independently hydrogen, azido, halo, methoxy, methyl, nitro and X is =0 in one step. The main object of the present invention is to provide a novel 2,3-diaryl(substituted)-4-(tert-butyl dimethylsilyloxy)-cyclopent-2-en-l-one and their derivatives. Another object of the present invention is to provide a process for the preparation of novel 2,3-diaryl(substituted)-4-(tert-butyl dimethylsilyloxy)-cyclopent-2-en-l-one and their derivatives in one step. Accordingly the present invention provides a 1 2,3-diphenyl (substituted)-4-(tert-butyldimethylsilyloxy)-cyclopent-2-en-l-one of the formula (1) wherein R1 to R9 are each independently selected from the group consisting of hydrogen, azido, halo, carboxymethyl, methoxy, methyl and nitro; X is =O or NOH. hydrogen, azido, halo, carboxymethyl, methoxy, methyl and nitro; X is =0 or NOH which comprises: mixing the compound of the formula (2) wherein R1 to R9 are each independently selected from the group consisting of hydrogen, azido, halo, carboxymethyl, methoxy, methyl and nitro; X is =0 or NOH with an aryl halide, a palladium salt, a phosphine salt, the phase transfer catalyst, and inorganic salt or organic base in a degassed solvent, heating the above said reaction mixture at a temperature in the range of 70 to 130°C for a period of 8 to 24 hrs followed by cooling to a temperature of 20-30°C, removing the solvent under reduced pressure, acidifying the residue and extracting the resultant residue with a water immiscible solvent, washing the above said residue extract with water and brine followed by drying over a drying agent, concentrating it to dryness under reduced pressure and purifying the residue by conventional method to obtain the product of formula (1). (Formula Removed) In an embodiment of the present invention the aryl halide used is selected from the group consisting of p-iodo anisole, 3,5-dimethyl-4-methoxy iodobenzene, 2,5-dimethoxy iodobenzene, methyl 3-iodo-6-methoxybenzoate, iodobenzene, 3,4-dimethoxyiodobenzene, 4- amino-3,5-difluoro-bromobenzene and 2,5-dimethoxyiodobenzene. In an another embodiment the palladium salt used is selected from palladium acetate, palladium chloride and Pd2(dba)3. In yet another embodiment the phosphine salt used is selected from the group consisting of tributylphosphine, triphenylphosphine and tri-(o-tolyl)-phosphine. In yet another embodiment the catalyst used is a phase transfer catalyst selected from the group consisting of tetrabutylammonium bromide, tetrabutyl-ammonium chloride, lithium chloride and cuprous iodide. The process of the present invention is described by the following examples, which are illustrative only and should not be construed as limit to the scope of the present invention in any manner. Example 1 Preparation of 2-(3,4,5-trimethoxyphenyl)-4-hydroxy-cyclopent-2-en-l-one of formula 2 as disclosed in our co-pending Indian patent application no. 0799del2002 General procedure : Magnesium (1.68 g, 70 mmol) was taken in three neck R.B. flask equipped with reflux condensor, and 100 ml ether followed by dibromoethane (9.5 g, 51.02 mmol) were added with stirring at 0°C under nitrogen atmosphere. Stirring was continued till all magnesium reacted, then ether was removed under vaccum till slurry was formed (A). In another single neck R.B. flask furan (4.76 g, 70 mmol) in tetrahydrofuran (100 ml) was cooled with ice-salt mixture, n-butyllithium (2M, 35 ml, 70 mmol) was added dropwise, and stirred at 0°C for 45 min (B). Fury lithium thus prepared in flask (B) was added to cold mixture in (A) through cannula, stirred at 0°C for 5 min, brought to room temperature and stirred at room temperature for 1.5 h and then cooled to -20°C (dry ice + CCl4). Substituted benzaldehyde (51.02 mmol) in tetrahydrofuran (50 ml) was added and stirred at -20°C for 4 h (monitored by TLC). After completion of reaction the mixture was quenched with saturated ammonium chloride solution. The mixture was allowed to warm to room temperature. Solvent was removed under reduced pressure and residue extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluents) to collect pure compounds aryl furfuryl alcohol of formula 3, wherein R1 and R5 are H and R2, R3 and R4 are OCH3 (Formula Removed) A solution of aryl rarfuryl alcohol wherein RI and R5 are H and R2, Ra and R4 are OCHa (25 g, 94.69 mmol) and ZnCl2 (51.26 g, 378.7 mmol) in dioxan (309 ml) and water (206 ml) was refluxed for 24 h at which time TLC analysis indicated the complete disappearance of starting material. The mixture was brought to room temperature, acidified to pH 1 with dilute HC1 and extracted with ethyl acetate. Organic layer was washed with water, followed by brine and dried over sodium sulphate. The organic layer was concentrated under reduced pressure using rotary evaporator and chromatographed on silica gel column to collect the required 2-(3,4,5- trimethoxyphenyl)-4-hydroxy-cyclopent-2-en-l-one of formula 2 (21.25g, 85%). Example 2 A mixture of p-iodo anisole (3.71 g, 15.87 mmol), cyclopentenone of the formula 2 ( 3.00 g, 7.93 mmol) wherein R2, R3 and R4 are methoxy, palladium acetate (0.230 g, 1.026 mmol), triphenyl phosphine, (0.40 g, 1.52 mmol), potassium carbonate (2.20 g, 15.86 mmol), and catalytic amount of tetrabutylammonium bromide (0.03 g) in degassed acetonitrile (50 ml) was refluxed for 36 h. The reaction mixture was cooled to room temperature, acetonitrile removed under reduced pressure using rotary evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform. Organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure, using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluent) to collect the pure product of the formula 1 (0.71 g, 66%) wherein R2, R3, R4 and R8 are methoxy. Example 3 A mixture of 3,5-dimethyl-4-methoxy iodobenzene (0.461 g, 1.75 mmol), cyclopentenone of the formula 2 (0.375 g, 0.99 mmol) wherein R2, R3 and R4 are methoxy, palladium acetate (0.026 g, 0.11 mmol), triphenyl phosphine, (0.06 g, 0.22 mmol), potassium carbonate (0.276 g, 2.0 mmol), and catalytic amount of tetrabutylammonium bromide (0.005 g) in degassed acetonitrile (8 ml) was refluxed for 36 h. The reaction mixture was cooled to room temperature, acetonitrile removed under reduced pressure using rotary evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform. Organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure, using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluent) to collect the pure product of the formula 1 ( 0.08 g, 26%) wherein R2, R3, R4, R8 are methoxy R7 and R9 are methyl. Example 4 A mixture of 2,5-dimethoxy iodobenzene (1.23 g, 4.65 mmol), cyclopentenone of the formula 2 (1.0 g, 2.64 mmol) wherein R2, R3 and R4 are methoxy, palladium acetate (0.071 g, 0.31 mmol), triphenyl phosphine, (0.15 g, 0.51 mmol), potassium carbonate (0.729 g, 5.28 mmol), and catalytic amount of tetrabutylammonium bromide (0.005 g) in degassed acetonitrile (20 ml) was refluxed for 36 h. The reaction mixture was cooled to room temperature, acetonitrile removed under reduced pressure using rotary evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform. Organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure, using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluent) to collect the pure product of the formula 1 ( 0.382 g, 56%) wherein R2, R3, R4, R6 and R9 are methoxy. Example 5 A mixture of iodobenzene (1.07 g, 5.29 mmol), cyclopentenone of the formula 2 (1.0 g, 2.64 mmol) wherein R2, R3 and R4 are methoxy, palladium acetate (0.071 g, 0.33 mmol), triphenyl phosphine, (0.150 g, 0.57 mmol), potassium carbonate (0.729 g, 5.28 mmol), and catalyticamount of tetrabutylammonium bromide (0.005 g) in degassed acetonitrile (20 ml) was refluxed for 36 h. The reaction mixture was cooled to room temperature, acetonitrile removed under reduced pressure using rotary evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform. Organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure, using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluent) to collect the pure product of the formula 1 ( 0.211 g, 35%) wherein R2, R3 and R4 are methoxy. Example 6 A mixture of methyl 3-iodo-6-methoxybenzoate (1,5 gm, 5.10 mmol), cyclopentenone of the formula 2 (1.2 g, 3.17 mmol) wherein R2, R3 and R4 are methoxy, palladium acetate (0.080 g, 0.35 mmol), potassium carbonate (0.874 g, 6.34 mmol), and catalytic amount of tetrabutylammonium bromide (0.02 g) in degassed acetonitrile (20 ml) was refluxed for 36 h. The reaction mixture was cooled to room temperature, acetonitrile removed under reduced pressure using rotary evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform. Organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure, using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluent) to collect the pure product of the formula 1 ( 0.28 g, 26.37%) wherein R2, R3, R4 ,R8 are methoxy and R9 is carboxymethyl. Example 7 A mixture of iodobenzene (2.12 g, 10.04 mmol), cyclopentenone of the formula 2 (1.5 g, mmol) wherein Rl, R2, R3, R4 and R5 are H, palladium acetate (0.135 g, 0.60 mmol), triphenyl phosphine, potassium carbonate (1.44 g, 10.4 mmol), and catalytic amount of tetrabutylammonium bromide (0.08 g) in degassed acetonitrile (30 ml) was refluxed for The reaction mixture was cooled to room temperature, acetonitrile removed under reduced pressure using rotary evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform. Organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure, using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluent) to collect the pure product of the formula 1 (0.10 g, 26%) wherein Rl to RIO are. Example 8 A mixture of 3,4-dimethoxyiodobenzene (2.46 g, 9.32 mmol), cyclopentenone of the formula 2 (0.5 g, 1.32 mmol) wherein R2, R3 and R4 are methoxy, palladium acetate (0.140 g, 0.625 mmol), triphenyl phosphine (0.30 g, 1.145 mmol), potassium carbonate (1.46 g, 10.5 mmol), and catalytic amount of tetrabutylammonium bromide (0.08 g) in degassed acetonitrile (20 ml) was refluxed for 36 h. The reaction mixture was cooled to room temperature, acetonitrile removed under reduced pressure using rotary evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform. Organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure, using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluent) to collect the pure product of the formula 1 ( 0.48 g, 29%) wherein R2, R3, R4, R7 and R8 are methoxy. Example 9 A mixture of 4-amino-3,5-difluoro-bromobenzene (0.512 g, 2.5 mmol), cyclopentenone formula 2 (0.95 g, 2.5 mmol) wherein R2, R3 and R4 are methoxy, palladium acetate (0.066 g, 0.29 mmol), triphenyl phosphine (0.156 g, 0.59 mmol), potassium carbonate (0.69 g, 5.0 mmol), and lithium chloride (1.25 g, 29.7 mmol) in degassed acetonitrile (20 ml) was refluxed for 24 h. The reaction mixture was cooled to room temperature, acetonitrile removed under reduced pressure using rotary evaporator. The residue was acidified with dilute HC1 and then extracted with dichloromethane. Organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure, using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluent) to collect the pure product of the formula 1 ( 0.41 g, 32.5%) wherein R2, R3, R4 are methoxy, R7 and R9 are fluoro, R8 is amino. Example 10 A mixture of iodobenzene (0.28 g, 1.37 mmol), cyclopentenone of the formula 2 (0.25 g, mmol) wherein R2 is nitro and R3 is methoxy, palladium acetate (0.018 g, 0.08 mmol), potassium carbonate (0.19 g, 1.37 mmol), and tetrabutylammonium bromide (0.10 g) in degassed acetonitrile (15 ml) was refluxed for 24 h. The reaction mixture was cooled to room temperature, acetonitrile removed under reduced pressure using rotary evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform. Organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure, using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluent) to collect the pure product of the formula 1 (0.048 g, 15.48%) wherein R2 is nitro and R3 is methoxy. Example 11 A mixture of 2,5-dimethoxyiodobenzene (0.36 g, 1.37 mmol), cyclopentenone of the formula 2 (0.25 g, 0.68 mmol) wherein R2 is nitro and R3 is methoxy, palladium acetate (0.018 g, 0.08 mmol), potassium carbonate (0.19 g, 1.37 mmol), and tetrabutylammonium bromide (0.10 g) in degassed acetonitrile (15 ml) was refluxed for 24 h. The reaction mixture was cooled room temperature, acetonitrile removed under reduced pressure using rotary evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform. Organic layer washed with water followed by brine, dried over sodium sulfate and concentrated to dryness under reduced pressure, using rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether : acetone as eluent) to collect the pure product of the formula 1 (0.10 g, 29%) wherein R2 is nitro, R3, R6 and R9 are methoxy. Example 11 Biological data of 2,3-diphenyl (substituted)-4-(ter?-butyldimethylsilyloxy)-cyclopent-2-en-lones of the formula (1), as a potential anti cancer compound, wherein RI, RS, R?, Rg and RIO are each independently = H and R2, R3, R4, Re and R9 =OCH3, X=O Example 12 Biological data of 2,3-diphenyl (substituted)-4-(ter?-butyldimethylsilyloxy)-cyclopent-2-en-lones of the formula (1), as a potential anti cancer compound, wherein RI to RIO are each independently = H and X=O ED 50 values (fig/ml) of in vitro cytotoxicity we claim 1. 2,3-diphenyI(substituted)-4-(tert-butyldimethylsilyloxy)-cyc!opent-2-en-1-ones of the formula (1) wherein Ri to R9 are each independently selected from the group consisting of hydrogen, azido, halo, carboxy methyl, methoxy, methyl and nitro;Xis=OorNOH. (Formula Removed) 2. 2,3-diphenyI(substituted)-4-(tert-butyldimethyIsHyloxy)-cyclopent-2-en-1 -ones of the formula (1) , substantially as herein described with reference to the examples accompanying this specification.

Documents:

792-DEL-2002-Abstract-(11-08-2008).pdf

792-del-2002-abstract.pdf

792-DEL-2002-Claims-(11-08-2008).pdf

792-del-2002-claims.pdf

792-del-2002-complete specification (granted).pdf

792-DEL-2002-Correspondence-Others-(03-10-2008).pdf

792-DEL-2002-Correspondence-Others-(11-08-2008).pdf

792-del-2002-correspondence-others.pdf

792-del-2002-correspondence-po.pdf

792-del-2002-description (complete)-03-10-2008.pdf

792-del-2002-description (complete)-11-08-2008.pdf

792-del-2002-description (complete).pdf

792-DEL-2002-Form-1-(11-08-2008).pdf

792-del-2002-form-1.pdf

792-del-2002-form-18.pdf

792-DEL-2002-Form-2-(11-08-2008).pdf

792-del-2002-form-2.pdf

792-DEL-2002-Form-3-(11-08-2008).pdf

792-del-2002-form-3.pdf