Process for producing γ -mangostin

1. A process for producing γ-mangostin from at least one O-methyl xanthone of general formula I, wherein each of R 1 , R 2 , R 3 , and R 4 is either H or CH 3 , with the proviso that at least one of R 1 , R 2 , R 3 , and R 4 is CH 3 ;

said process comprising the steps of:

(i) subjecting said at least one O-methyl xanthone to a demethylation reaction using a demethylating reagent, and

(ii) purifying the said reaction product to obtain pure γ-mangostin;

wherein the demethylating reagent comprises an organic base and a Lewis acid.

2. The process as claimed in claim 1 , wherein said Lewis acid is selected from the group consisting of aluminum chloride, aluminum bromide, aluminum iodide, boron tribromide, boron trichloride-methyl sulfide complex, boron trichloride, boron trifluoride, zinc chloride and iron chloride.

3. The process as claimed in claim 1 , wherein the demethylating reagent is used with a catalyst, said catalyst being:

a metal iodide selected from the group consisting of sodium iodide, potassium iodide, magnesium iodide, calcium iodide; or

a phase transfer catalyst.

4. The process as claimed in claim 1 , wherein said organic base is selected from the group consisting of pyridine, triethylamine, N,N-diethylaniline, and N, N-dimethylaniline.

5. A process for producing γ-mangostin as claimed in claim 1 , comprising the steps of:

Step 1: preparation of pure O-methyl xanthone, semi pure O-methyl xanthone or mixtures of O-methyl xanthones of the general formula I, from a plant source selected from the group consisting of Garcinia mangostana, Garcinia cowa, Garcinia dulcis, Garcinia fusca, Garcinia speciosa, Hydnocarpus species, Cratoxylum formosurn, Allanblackia monticola, Cratoxylurn cochinchinense , and mixtures thereof;

Step 2: dissolving said pure O-methyl xanthone, said semi pure O-methyl xanthone or said mixtures of O-methyl xanthones of the general formula I in an organic solvent to produce a solution;

Step 3: treating the solution with an organic base and stabilizing the solution for a suitable period of time;

Step 4: subsequent to step (3), treating the solution with a Lewis acid and optionally with a catalyst at room temperature to produce a reaction mixture, followed by refluxing the reaction mixture for a suitable period of time, until said pure O-methyl xanthone, said semi pure O-methyl xanthone or said mixtures of O-methyl xanthones are converted to γ-mangostin;

Step 5: quenching the reaction by pouring the reaction mixture into a mixture of ice water, an acid, and brine;

Step 6: extracting the said acidified reaction mixture with an organic solvent; and

Step 7: adding an organic base, to the organic layer prior to evaporating the solvent under vacuum to yield γ-mangostin.

6. The process as claimed in claim 5 , wherein said Lewis acid in step 4 is selected from the group consisting of aluminum chloride, aluminum bromide, aluminum iodide, boron tribromide, boron trichloride-methyl sulfide complex, boron trichloride, boron trifluoride, zinc chloride or iron chloride.

7. The process as claimed in claim 5 , wherein the catalyst is a metal iodide selected from the group consisting of sodium iodide, potassium iodide, magnesium iodide, calcium iodide or a phase transfer catalyst like tetrabutylammonium bromide.

8. The process as claimed in claim 5 , wherein said organic solvent used in step 2 is selected from the group consisting of dichloromethane, dichloroethane, or ethyl acetate.

9. The process as claimed in claim 5 , wherein said organic base used in step 3 is selected from the group consisting of pyridine, triethylamine, N,N-diethylaniline, and N,N-dimethylaniline.

10. The process as claimed in claim 5 , wherein said organic base used in step 7 is selected from the group consisting of pyridine, triethylamine, N,N-diethylaniline, and N,N-dimethylaniline.

11. The process as claimed in claim 5 , further comprising purifying γ-mangostin by subjecting the γ-mangostin to column chromatography on a solid support;

wherein the solid support for column chromatography is selected from the group consisting of silica gel, reversed phase silica gel, styrene-divinylbenzene resin, R20 resin or anion exchange resin.

12. A process for producing γ-mangostin as claimed in claim 1 , wherein:

a) said at least one O-methyl xanthone is a mixture comprising 10-40% by wt. of α-mangostin, 0.5-2% by wt. of β-mangostin and 0.1-0.5% by wt. of γ-mangostin;

b) said step (i) comprises demethylating said at least one O-methyl xanthone to produce a product containing 10-40% by wt. of γ-mangostin; and

c) said step (ii) comprises purifying said product by at least one of chromatography and crystallization to produce γ-mangostin having a purity of 90-99% by wt.

13. A process for producing γ-mangostin as in claim 1 , wherein:

a) said at least one O-methyl xanthone comprise 40-70% by wt. of α-mangostin;

b) said step (i) comprises demethylating said at least one O-methyl xanthone to produce a product containing 40-70% by wt. of γ-mangostin; and

c) said step (ii) comprises purifying said product by at least one of chromatography and crystallization to produce γ-mangostin having a purity of 90-99% by wt.

14. A process for producing γ-mangostin as in claim 1 , wherein:

a) said at least one O-methyl xanthone comprise 70-95% by wt. of α-mangostin;

b) said step (i) comprises demethylating said at least one O-methyl xanthone to produce a product containing 70-95% by wt. of γ-mangostin; and

c) said step (ii) comprises purifying said product by at least one of chromatography and crystallization to produce γ-mangostin having a purity of 90-99% by wt.

15. A process for producing γ-mangostin as in claim 1 , wherein:

a) said at least one O-methyl xanthone comprise 95-99% by wt. of α-mangostin;

b) said step (i) comprises demethylating said at least one O-methyl xanthone to produce a product containing 95-99% by wt. of γ-mangostin; and

c) said step (ii) comprises purifying said product by at least one of chromatography and crystallization to produce γ-mangostin having a purity of 99% by wt.

16. A process for producing γ-mangostin as in claim 1 , wherein:

a) said at least one O-methyl xanthone comprise 99% by wt. of α-mangostin;

b) said step (i) comprises demethylating said at least one O-methyl xanthone to produce a product containing more than 99% by wt. of γ-mangostin.

17. A process for producing γ-mangostin, from at least one O-methyl xanthone other than α-mangostin, wherein said at least one O-methyl xanthone is first converted to α-mangostin by a first demethylating reagent and the α-mangostin so obtained is then demethylated using a second demethylating agent comprising an organic base and a Lewis acid to obtain γ-mangostin.

18. A process as claimed in claim 17 , wherein the first demethylating reagent for producing α-mangostin is sodium cyanide in dimethylsulfoxide.

19. A process for producing γ-mangostin from at least one O-methylxanthone of general formula I, wherein each of R 1 , R 2 , R 3 , and R 4 is either H or CH 3 , wherein a) at least one of R 1 , R 2 , R 3 , and R 4 is CH 3 , and b) said at least one O-methylxanthone is not α-mangostin;

said method comprising:

demethylating said at least one O-methylxanthone with a first demethylating agent to produce α-mangostin; and

demethylating said α-mangostin with a second demethylating agent to produce γ-mangostin, said second demethylating agent comprising an organic base and a Lewis acid.

20. A process for producing γ-mangostin as claimed in claim 19 , wherein said at least one O-methyl xanthone comprises a compound selected from the group consisting of; 1,6-dihydroxy-3,7-dimethoxy-2,8-bis-(3-methyl-but-2-enyl)-xanthen-9-one (β-mangostin, R 1 ═R 3 ═H, R 2 ═R 4 ═CH 3 ); 1,3-dihydroxy-6,7-dimethoxy-2,8-bis-(3-methyl-but-2-enyl)-xanthen-9-one (R 1 ═R 2 ═H, R 3 ═R 4 ═CH 3 ); 1-hydroxy-3,6,7-trimethoxy-2,8-bis-(3-methyl-but-2-enyl)-xanthen-9-one (R 1 ═H, R 2 ═R 3 ═R 4 ═CH 3 ); and mixtures thereof.

21. A process for producing γ-mangostin as claimed in claim 19 , wherein said at least one O-methyl xanthone is derived from a plant selected from Garcinia mangostana, Garcinia cowa, Garcinia dulcis, Garcinia fusca, Garcinia speciosa, Hydnocarpus species, Cratoxylum formosum, Allanblackia monticola, Cratoxylum cochinchinense.

22. A process for producing γ-mangostin as claimed in claim 19 wherein said at least one O-methyl xanthone, is of semisynthetic origin obtained from xanthones isolated from a plant selected from Garcinia mangostana, Garcinia cowa, Garcinia dulcin, Garcinia fusca, Garcinia speciosa, Hydnocarpus species, Cratoxylum formosum, Allanblackia monticola, Cratoxylum cochinchinense.

23. A process for producing γ-mangostin as claimed in claim 19 , wherein said at least one O-methyl xanthone is a pure compound or a partially pure compound obtained as a plant extract or an enriched plant extract or a mixture having the chemical structure(s) corresponding to the general formula I.

24. A process for producing γ-mangostin as claimed in claim 19 , wherein the concentration of said at least one O-methyl xanthone in the starting mixture is in the range of 5% to 99%.

25. A process for producing γ-mangostin as in claim 23 , wherein the concentration of said at least one O-methyl xanthone in the starting mixture is in the range of 5% to 99%.