Title of Invention	"A PROCESS OF PREPARING A NOVEL CHIRAL ESTER DERIVATIVE OF GARCINIA ACID BEARING LACTONE MOIETY"
Abstract	A novel acyclic chiral compound of Garcinia acid wherein, R3- R5- -C(4-MePh)2OH; R3- -CH2C(4-MePh)2OH

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Field of Invention This invention relates to novel chiral derivatives bearing lactone moiety of Garcinia acid and a process for preparing the same. Background of the invention: Garcinia acid [(-)-Hydroxycitric acid lactone or (2S,3S)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarb6xylic acid] is isolated from the fruits of Garcinia cambogia,Garcinia indica and Garcinia atroviridis. Garcinaia acid for formula la is widely used as an important ingredient in many pharmaceuticai formulations 1-10. The non-availability of la in the market, in the pure form, has resulted in the limited use of these compounds in the area of organic synthesis and pharmaceutical front . This is due to the lack of any commercially viable large-sca.le manufacturing process. In US patent application No. 09/365,301,1999 an economic, commercially viable, cost effective process for the large- scale isolation of la has been described11 . Also during the past two decades there has been a great deal of interest to find cheap and potential chiral molecules from chiral pool to accomplish synthetic pathways with a high degree of asymmetric induction 12-25. Added to this, substituted -butyrolactones are known to be potent antagonists or agonists depending upon the substitution pattern of the -aminobutyric acid receptor, the major inhibitory neurotransmitter in the mammalian central nervous system 26. The known methods for obtaining diversity functionalised chiral -lactones are either by the cyclisation of acyclic starting materials such as the sterioselective iodolactonisation of unsaturated 3-hydroxy acids27 or from sugars such as D-ribofuranose or D-glucosamine or carbohydrates such as D-ribose, D-glucose etc28. These chemical modifications involving carbohydrates require tedious protocols. The object of this invention therefore is to prepare novel chiral derivatives of Garcinia acid and the process of preparing the same. To achieve the objective this invention provides a process of preparing novel chiral ester derivatives of Garcinia acid bearing lactone ring moiety of formula I- (Formula Removed) wherein: R1 =R3 - lower esters , -COOC2H5, -COOCH(CH3)2 R2 = hydroxyl or protected hydroxyl group, comprising - adding organic halide to a suspension of Formula Ib as herein described in appropriate alcohol, - stirring the mixture for 24 to 36 hours - neutralizing the mixture with aqueous alkalisolution, - extracting the said mixture using organic solvent, - evaporating and extracting using an appropriate organic solvent yielding compound of formulal as a yellow oil. (Formula Removed) Summary of the chiral derivatives of Garcinia acid bearing lactone ring moiety is given below in scheme I: SCHEME I (Scheme Removed) The present invention further provides a process of preparation of Formula Ib comprising: treating an aqueous solution of Ia with an aqueous solution of alkali till the pH of the solution is neutral, evaporating the solution to dryness. washing the residue with water miscible organic solvent drying the product Ib in vaccum. The said alkali is sodium bicarbonate. The invention further includes a process for the preparation of novel chiial derivative of formula Ic, comprising: adding an organic halide to a suspension of Ib in organic solvent, stirring the mixture for 1-4 hours, filtering the said mixture, evaporating the said solution to get Ic as a hygroscopic solid. The said organic solvent is ether. The said organic halide is thionyl chloride. The invention further includes a process for the preparation of novel chiral derivative of formula Id comprising: adding DMSO, an organic acid and an anhydride to If. allowing the mixture to stand for 3-4days, adding the reaction mixture to cold saturated aqueous solution of alkali, stirring the mixture for l-4hours, extracting the resultant solution with an organic solvent, washing the extract with aqueous alkali, drying the organic layer, evaporating to get crude Id, purifying the crude Id by chromatography to get pure Id as an yellow oil. The said organic acid is acetic acid. The said anhydride is acetic anhydride. The said alkali is sodium bicarbonate. The said organic solvent used for extraction is chloroform. The invention further includes a process for the preparation of novel chiral derivative of formula le comprising: refluxing la with an appropriate alcohol and organic acid in toluene for 10-20 hours using Dean-Stark set up, washing the mixture with aqueous alkali solution, evaporating the organic phase, recrystallising from organic solvents or their appropriate mixtures yielding le as a solid. The said appropriate alcohol is benzyl alcohol. The said anhydride is acetic anhydride. The said alkali is sodium bicarbonate. The said organic solvent used for crystallization is selected from hexane or ether. The invention further includes a process of preparation of novel chiral derivative of formula Ig comprising: adding organic halide to a suspension of Ib in absolute alcohol,stirring the mixture for 24 hours, neutralizing the mixture with aqueous alkali solution, extracting the said mixture using organic solvent, evaporating the mixture furnishing Ig as a yellow oil. The said organic halide is thionyl chloride. The said alcohol is ethanol. The said alkali is sodium bicarbonate. The said organic solvent is chloroform. The invention further includes a process of preparation of novel chiral derivative of formula Ih comprising: adding an organic halide to a suspension of Ib in appropriate dry alcohol, stirring the mixture for 36 hours, neutralizing with aqueous alkali solution, extracting the said solution with an organic solvent. evaporating and extracting using an appropriate organic solvent yielding Ih as a yellow oil. The said organic halide is thionyl chloride. The said appropriate alcohol is isopropyl alcohol. The said appropriate allcali is sodium bicarbonate. The said appropriate organic solvent is chloroform. The organic solvent used after evaporation is hexane. The invention further includes a process of preparation of novel chiral derivative of formula Ij comprising: refluxing the suspension of Ia in an organic halide for 3 hours,concentrating the said mixture under vacuum, dissolving the solid obtained in an organic solvent, adding an appropriate amine to the dissolved solution, stirring the mixture at room temperature for 4-18 hours, concentrating the solution under vacuum, adding the organic halide to the semi-solid obtained, refluxing for 18 hours, extracting with suitable organic solvent, subjecting the said extract to chromatography furnishing Ij as white crystals, The said organic halide is acetyl chloride. The said appropriate amine is 4-methoxy benzyl amine. The said organic solvent is chloroform. The process will now be described with reference to the following examples. Example 1: Garcinia acid (Ia) Dried rinds of the fruits of Garcinia cambogia (2.0 Kg) were cut into small pieces and soaked in hot water. The extract was collected after 20 hours and the process was repeated (4-5 times). The combined extract was concentrated to get a thick mass to which methanol was added. The precipitated pectin was filtered off and the filtrate was further concentrated to a syrup. The syrup was made alkaline by adding sufficient quantity of aqueous sodium; hydroxide solution followed by the addition of methanol till two layers separated. The separated sodium salt of la (lower layer) was washed several times with aqueous methanol. The pure sodium salt was dissolved in sufficient quantity' of 2N hydrochloric acid. To the concentrated solution acetone was added to remove insoluble impurities. The filtrate on concentration yielded crude erystals of Garcinia acid. Upon recrystallisation from acetone-chloroform mixture yielded crystals of la in high purity. Melting point -.1780 C. Yield : 135.0g Example2: Disodium(2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (Ib) : To an aqueous solution of Ia (2.0 g, 10.5 mmol, in 10 ml water) saturated sodium bicarbonate solution was added till the pH of the solution is neutral. The residue obtained after evaporation was washed with dry acetone (5 x 20 ml). The product Ib was finally dried under vacuum. Yield : 2.0 g (82%). Examples: (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarbonylchloride (Ic) To a suspension of Ib (1.0 g, 4.4 mmol) in ether (10 ml), thionyl chloride ( 1.0 ml, 14 mmol) was added. The mixture was stirred for two hours. Filtration followed by evaporation of the reaction mixture yielded Ic . Yield : 0.75g (65%). Example 4: Dimethyl(2S,3S)-tetrahydro-3-oxo-{(methylthio)methoxy]-5-oxo-2,3-furandicarboxylate (Id) : To a solution of If (2 g, 9.2 mmol) in DMSO (28 ml), acetic acid (3.5 ml) in acetic anhydride (20 ml) was added. The mixture was allowed to stand for three days. The reaction mixture was added to saturated aqueous solution of sodium bicarbonate (400 ml) and stirred for one hour. It was extracted with chloroform (3 x 125 ml) and the combined chloroform extracts was washed with saturated sodium bicarbonate solution (100 ml) followed by water (2 x 50 ml). The chloroform extract was dried (sodium sulphate) and evaporated to get crude Id (1.5 g). Id was further purified by column chromatography (silicagel 60-120 mesh, eluent: hexane-chloroform, 10-50%) Yield: ft 75 g (29%) Example 5: Bis(phenylmethyl)(2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (le) la (3.8 g, 20 mmol) was refluxed with benzyl alcohol (6.5 g, 60 mmol) and p-toluene sulphonic acid (50 mg, 0.25 mmol) in toluene (40 ml) for 13 hours using a Dean- Stark set up. The mixture was washed with aqueous sodium bicarbonate solution (50 ml). The aqueous phase was extracted using chloroform (20 m]). Evaporation of the combined extracts yielded le which was recrystallised from hexane-ether. Melting point: 81-82 °C Yield: 5.2g (70%) Example 6: Diethyl (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylate (Ig): To a precooled (-5 - 00C) suspension of Ib (1.0 g, 4.4 mmol) in dry ethanol (10 ml), thionyl chloride ( 0.7 ml, 10 mmol) was,added. The mixture was then stirred for 24 hours at room temperature. After filtration of the reaction mixture, pH of the filtrate was adjusted to 7.0, by adding saturated aqueous solution of sodium bicarbonate and was extracted with chloroform (3 x 10 ml). The combined extract upon drying and evaporation furnished an oily residue of Ig. Yield :0.9g(77%) Example?: Diisopropyl (2S,3S)-tetrahydro-3-hydrory-5-oxo-2,3-furandicarboxylate (Ih) To a precooled (-5 - 0° C) suspension of Ib (1.0 g, 4.4 mmol) in isopropyl alcohol (10 mi) and thionyl chloride ( 0.7 ml, 10 mmol) was added. The mixture was then stined for 36 hours at room temperature. After filtration of the reaction mixture, pH of the filtrate was adjusted to 7.0. by adding saturated aqueous solution of sodium bicarbonate and was extracted with chloroform (3 x 10 ml). The organic layer was concentrated and extracted using hexane. The combined extract upon dning and evaporation furnished an oily residue of Ih. Yield :0.5g(41%) Example 8: (3aS,6aS)-3a-(acetyloxy)dihydro5(phenylmethyl)6Hfuro[2,3-c]pyrrole-2,4,6 (3H,4H)-trione) (Ii). A suspension of la (1g. 5 mmol) in acet\l chloride (4 ml) was refluxed for 3 hours followed by concentration under vacuum.The solid obtained was dissolved in THF (5ml) and benzyl amine (0.535ml, 5 mmol) vvas added. The mixture was stined at room temperature for 4 hours and concentrated in vacuum. To the semisolid obtained acetyl chloride (5 ml) was added and the mixture was refluxed for 18 hours. Extraction using ethyl acetate followed by recrystallisation from hexane - ethyl acetate furnished Ii as white cnstals. Melting point: 156-157 0 C Yield : 0.75g (52%) Uses: Pharmaceutical applications Chiral derivatives, la-Ik, are used as chiral synthons We claim: 1. A process of preparing novel chiral ester derivative of Garcinia acid bearing lactone ring moiety of formula I, (Formula Removed) wherein: R1 = R3 = lower esters , -COOC2H5, -COOCH(CH3)2, R2 = hydroxyl or protected hydroxyl group, comprising - adding organic halide ito a suspension of Formula Ib as herein described in appropriate alcohol, - stirring the mixture for 24 to 36 hours - neutralizing the mixture with aqueous alkali solution, - extracting the said mixture using organic solvent, - evaporating and extracting using an -appropriate organic solvent yielding compound of formula I as a yellow oil. (Formula Removed) 2. A process of preparation of novel chiral ester derivative as claimed in claim 1, wherein R1 =R3 = -COOC2H5, R2 - -OH to obtain the compound of formula Ig comprising: adding organic halide to a suspension of Ib in appropriate alcohol, stirring the mixture for 24 hours, neutralizing the mixture with aqueous alkali solution, extracting the said mixture using organic solvent, evaporating the mixture furnishing Ig as a yellow oil. (Formula Removed) 3. A process of preparation of novel chiral ester derivative as claimed in claim 1, wherein R1=R3= -COOCH(CH3)2, R2= -OH to obtain compound of formula Ih comprising: adding an organic halide to a suspension of Ib in appropriate dry alcohol, stirring the mixture for 36 hours, neutralizing with aqueous alkali solution, extracting the said solution with an organic solvent. evaporating and extracting using an appropriate organic solvent yielding Ih as a yellow oil. (Formula Removed) 4. A process as claimed in claim 1 to 3 wherein, the organic halide is thionyl chloride. 5. A process as claimed in claims 1 to 3 wherein, the said organic solvent used for extraction is chloroform. 6. A process as claimed in claim 2 wherein, the said alcohol is ethanol. 7. A process as claimed in claim 3 wherein, the said alcohol is isopropyl alcohol. 8. A process as claimed in claim 3, wherein the organic solvent used after evaporation is hexane. 9. A process of preparing a novel chiral derivative of Garcinia acid bearing lactone moiety of formula I substantially as herein described with reference to the foregoing examples.

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1426-del-2003-abstract.pdf

1426-del-2003-claims-cancelled.pdf

1426-del-2003-claims.pdf

1426-del-2003-complete specification(granted).pdf

1426-del-2003-correspondence-others.pdf

1426-del-2003-correspondence-po.pdf

1426-del-2003-description (complete).pdf

1426-del-2003-form-1.pdf

1426-del-2003-form-19.pdf

1426-del-2003-form-2.pdf

1426-del-2003-form-3.pdf

1426-del-2003-gpa.pdf

1426-del-2003-petition-138.pdf

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