Title of Invention

"A NOVEL ACYCLIC CHIRAL ALWHELS OF GARCINIA ACID AND A PROCESS FOR PREPARING THE SAME"

Abstract

A process of preparing a novel chiral derivative of Garcinia acid bearing lactone moiety of formula 1, R1=R3 , alkali salt of carboxyl acid, or acid chloride or lower esters or part of N-substituted cyclic imides. R2 = hvdroxyl or protected hydroxyl group. and more specificall)r compound of formula lb wherein R1 = R3 = -COONa, R2 OH and said derivative is Disodiuin(2S ,3 S)-terrahydro-3-hydroxy-5-oxo-2 ,3 - furandicarboxylate. comprising the steps - 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 lb in vacuum.

Full Text

This invention relates to novel acyclic chiral derivatives of Garcinia acid and the process of preparing the same. Background of the invention: Garcinia acid [(-)-Hydroxycitric acid lactone or (2S,3S)-Tetrahydro-3-hydroxy-5-oxo-2.3-furandicarboxyhc acid] is isolated from the fruits of Garcinia cambogia,Garcinia indica and Garcinia atroviridis. This molecule is widely used as an important ingredient in many pharmaceutical formulations. The non-availability of Garcinia acid in the market, in the pure form, has resulted in the limited use of these compounds in the area of organic SMithesis and pharmaceutical front. This is due to the lack of any commercially viable large-scale manufacturing process.In US patent application No. 09/365.300 economic, commercially viable, cost effective process for the large- scale isolation of Garcinia acid has been described. The object of the present invention is to prepare hitherto unknown acyclic chiral molecules from Garcinia acid. To achieve the said objective this invention provides novel chiral derivatives of Garcinia acid of formula I Formula I wherein: R2=R5:=lower aryl/alkyl ester or substituted aryl/alkyl alcohol R3- substituted aryl/alkyl ester or substituted aryl alcohol R1=R4 =hydroxy 1 or In the above formula I R2 an R5 is selected from -COOCH3,-COOC2H5, -COOCH(CH3)2 C(Ph)2OH, -C(4-MePh)2OH, -C( 1-Naphth)2OH R, and R, is Oil or R3 is selected from -CH2COOCH3. -CH2COOC2Ik -CH2COOCH(CH3)2. -CH2C(Ph)2OH. -CH2C(4-MePh)2OH. -CH2C( 1 -Naphth)2OH to form various chiral derivatives, namely, chiral triesters. chiral ketals and chiral alcohols. Chiral tries ter derivatives: (Scheme Removed) Chiral ketal derivatives: (Scheme Removed) Chiral alcohol derivatives (diols): (Scheme Removed) Summary of the chiral derivatives of Garcinia acid is given below in scheme I: SCHEME I (Scheme Removed) The present invention further provides a process for preparing the chiral triester derivatives of formulae comprising: refluxing garcinia acid with appropriate alcohol in presence of an inorganic catalyst for 6-12 hours, adjusting the pH of the reaction-mixture using aqueous alkali solution, concentrating the said reaction-mixture by evaporation, extracting the said concentrate with an organic solvent. The said appropriate alcohols are selected from methanol, ethanol and isopropanol. The said catalyst is cone.HCl. The said organic solvent is chloroform. The present invention further includes a process for preparing the chiral alcohol derivatives of formulae If to Ih comprising: adding solution of chiral acetal/ketal in an organic solvent to a soution of appropriate grignard reagent(ArMgX) in an organic solvent. refluxing the mixture for 10-20 hours, adding the inorganic salt solution to the chilled reaction mixture. collecting the organic phase and extracting the aqueous layer further with an organic acid, drying the organic extract using an inorganic salt, evaporating the said extract, subjecting the residue to chromatography. The organic solvent is tetra hydro furan (THF). The said appropriate grignard reagent is phenyl Mg bromide, methylphenyl Mg bromide, naphthyl Mg bromide. The said inorganic salt is ammonium chloride and organic solvent used for extraction is ether. The salt used for drying the extract is sodium sulphate. 1 he chromatography emploved for purification is column chromatography. The gel used for chromatography is silica gel. The eluant used for chromatography is hexane-chloroform mixture. Chiral ketals were prepared using standard procedures. The invention will now be described with reference to the following examples: Chiral triester derivatives: Example l: I rimethyl (lS,2S)-l,2-dihydroxy-l,2,3-propanetricarboxylate (la): (iarcinia acid (5.0 g, 2,6.3 mmol) was retluxed with methanol (100 ml) and cone. HCl (3 ml) for 12 hours. pH of the reaction mixture was adjusted to neutral using aqueous solution of sodium bicarbonate. The resultant solution was evaporated and extracted with chloroform (4 x 50 ml). The combined chloroform extracts was dried (sodium sulphate) and on concentration furnished la. Yield: 2.0 g (30%) Example 2: Triethyl (1 S,2S)-1,2-dihydroxy-1,2,3-propanetricarboxylate (lb): lb was prepared from Garcinia acid and ethanol in 46% yield by the same procedure used to prepare la from Garcinia acid. Example3: Triisopropyl(l S,2S)-1,2-dihy droxy-1,2,3-propanetricarboxylate (Ic): Ic was prepared from Garcinia acid and dry isopropanol by the same procedure used to prepare la from Garcinia acid. Melting point: 128° C Yield : 4.0 g (66%) Example 4: I)iniethvI(4S,5S)-2,2-dimethyl-4-(2-oxo-2-methoxvethvl)-l,3-dioxoiane-4,5-dicarboxylate (Id): To la (2.0 g. 8 mmol) in dry acetone (50 ml), anhydrous copper sulphate (1.0 g) and a few drops of cone, sulphuric acid were added .The mixture was re fluxed for four hours, followed by filtration and neutralisation using aqueous sodium bicarbonate solution. The resultant solution obtained after evaporation was extracted with hexane (4 x 25 ml). The combined extracts after washing with water (50 ml) was dried with sodium sulphate. Upon evaporation. Id obtained as an yellow oil. Yield: 0.5g (22%) Example 5 : Diethyl (4S,5S)-2,2-dimethyl-4-(2-oxo-2-ethoxyethyl)-l,3-dioxolane-4,5-dicarboxylate (Ie): Ie was prepared from lb in 44% yield by the same procedure used to prepare Id from la. Kxample6: (4S,5S)-4-(2-hydroxy-2,2-diphenylethyI)-2,2-dimethyl- alpha,alpha,alpha%alpha^etraphenyI43-dioxolane-4,5-dimethanol (II): A solution of Id (lg, 3.4 mmol, in 7 ml THF) was added to a solution of Phenyl magnesium bromide in THF (20 ml. 1M) and the mixture was refluxed for 15 hours. To the chilled reaction mixture aqueous "ammonium chloride solution (20 ml) was added. The organic phase was collected and the aqueous layer was extracted with ether (5 x 10 ml). The combined organic phase was dried (sodium sulphate). The solution upon evaporation followed by column chromatography (silica gel 60-120 mesh, eluent: hexane) yielded If. Yield : 1.0% I'SKS: pharmaceutical applications . chiral derivatives la-Ic and If-Ih is used for the preparation of chiral catalyst and chiral auxiliaries. . The derivatives of la-Ih is used as chiral svnthons We Claim: 1. A process for preparing the chiral alcohols of formula If to Ih having a general formula (Formula Removed) Formula I wherein, (Formula Removed) - adding solution of chiral acetal or ketal in an organic solvent to a soution of appropriate grignard reagent(ArMgX) in an organic solvent, - refluxing the mixture for 10-20 hours, - adding the inorganic salt solution to the chilled reaction mixture, - collecting the organic phase and extracting the aqueous layer further with an organic acid, - drying the organic extract using an inorganic salt, - evaporating the said extract, - subjecting the residue to chromatography. 2 A process as claimed in claim I wherein, the organic solvent is tetra hydrofuran (THE). 3. A process as claimed in claim 1 wherein, the said appropriate grignard reagent is phenyl Mg bromide, methyiphenyl Mg bromide, naphthyl Mg bromide. 4. A process as claimed in claim 1 wherein, the said inorganic salt is ammonium chloride. 5. A process as claimed in claim 1 wherein, the said organic solvent used for extraction is ether. 6. A process as claimed in claim I wherein, the said salt used for drying the extract is sodium sulphate. 7. A process as claimed in claim 1 wherein, the chromatography employed for purification is column chromatography. 8. A process as claimed in claim 1 wherein, the gel used for chromatography is silica gel. 9. A process as claimed in claim 1 wherein, the eluant used for chromatography is hexane-chiloroform mixture.

Documents:

1427-del-2003-abstract.pdf

1427-del-2003-claims.pdf

1427-del-2003-complete specification (granted).pdf

1427-del-2003-correspondence-others.pdf

1427-del-2003-correspondence-po.pdf

1427-del-2003-description (complete).pdf

1427-del-2003-form-1.pdf

1427-del-2003-form-19.pdf

1427-del-2003-form-2.pdf

1427-del-2003-form-3.pdf

1427-del-2003-gpa.pdf

1427-del-2003-petition-138.pdf

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