MXPA97003371A

MXPA97003371A - Improved processes for the preparation of d-quiro-inosi

Info

Publication number: MXPA97003371A
Application number: MXPA/A/1997/003371A
Authority: MX
Inventors: A Riley David; A Chamberlin Steven
Original assignee: Abbott Laboratories
Priority date: 1994-11-10
Filing date: 1995-11-09
Publication date: 1997-08-01

Abstract

The present invention relates to a method for the preparation of D-chiro-inositol (I), comprising the steps of: (a) reacting kasugamycin with an acetylating agent to form an intermediate of crude hexa-acetate; b) purifying the crude intermediate to form the purified hexa-acetate intermediate, (c) deacetylating the purified intermediate to form D-chiro-inositol, and (d) isolating D-chiro-inositol. The method allows the large-scale, efficient preparation of D-chiro-inositol without the need for extensive chromatographic purification of the D-chiro-inositol product.

Description

IMPROVED PROCESSES FOR THE PREPARATION OF D-Q (HflO-INOSITOL Background of the I nvention D-a / w ro-inosítol and myo-inositol, which has respectively the structural formulas of natural occurrence, with the most abundant m / o-isomer found generally in plants such as hexaphosphate, phytic acid or as salts of hexaphosphate, phytin. In mammals, the mono- and polyphosphate forms are those components that are components of cell membranes and can function as insulin mediators. Following the observation that the conversion of my to qru / ro-inositol is deficient in mammals suffering from certain types of diabetes, it has been proposed more recently that supplementing the diet with Dq / v / ro-inositol can help control the glucose levels in the blood of patients affected by this disease.

The need for research and commercial quantities of D-qriv'ro-inositol has led to the development of several methods for isolation (by extraction from plant tissues), partial synthesis or complete synthesis of that compound. The hydrolysis of aminogliside kasugamicin (produced by fermentation of Streptomyces kasugaspinus) is especially promising as described in U.S. Patent No. 5,091,596 issued to Kennington et al. According to that patent, kasugamycin is treated with trifluoroacetic acid for 3 hours at 100 ° C, after which the resulting D-chiro-inositol is isolated by resin and gel chromatography and purified by recrystallization from 90% ethanol. %. Alternatively, kasugamycin can be treated with hydrochloric acid for 8 hours at 90 ° C, followed by isolation of D-qru ro-inositol by means of resin chromatography and subsequent purification. However, when larger amounts of the product are prepared, a relative disadvantage of each of the above acid hydrolysis processes is the cost of the isolation step by chromatography in which D-o / u / ro-inositol is purified. Similarly, isolating the D-qfu / ro-inositol product from a dilute aqueous solution, such as lyophilization, can be unduly time consuming when carried out as a part of an industrial process.

Consequently, there is still a need for more efficient methods by which high purity D-u-ω-inositol can be prepared, economically and on a large scale, from kasugamycin.

Brief Description of the Invention It has now been found that D-qu / ro-inositol can be obtained from kasugamycin via a substantially more efficient pathway, ie by acetolysis of the aminoglycoside to form hexa-O-acetyl-Do / v / ro-inositol intermediary ("hexa-acetate"). This hexa-acetate is easily isolated and purified before deacetylation of the intermediate. In addition, deacetylation of the intermediate hexaacetate can be carried out under conditions that allow the immediate crystallization of D-gu ro-inositol in a significantly pure form, eliminating the need for extensive purification of the final product. In general, the semi-synthesis of the present invention produces the D-? R? / Ro-inositol of satisfactory purity without purification of chromatography and, therefore, with time and cost savings when compared to previously described methods. . Accordingly, the present invention comprises a method for the preparation of D-β ru / ro-inositol from kasugamycin, comprising the steps of: (a) reacting kasugamycin with an acetylating agent to form hexa-acetate raw; (b) purifying the crude hexa-acetate to form the purified hexa-acetate; (c) deacetylating the purified hexa-acetate to form the D-qu ro-inositol; and (d) isolate D-gu / ro-inositol. The D-β-rho-inositol isolated in the above fourth step can optionally be subjected to an additional step, wherein the D-chiro-inositol is further purified by recrystallization. In addition, the second step (purification of crude hexa-acetate) can comprise a number of particular sub-steps, namely: (i) substantially removing the acetylating agent to form a residue; (ii) dilute the residue in a suitable solvent system to form a crude hexa-acetate solution; (iii) filtering the crude hexa-acetate solution to form a purified hexa-acetate solution; and (iv) substantially remove the solvent. An additional sub-step may optionally be included, between the sub-steps (ii) and (iii), wherein the solution of the crude hexa-acetate is neutralized before filtration. Alternatively, the optional neutralization sub-step may take place between sub-steps (iii) and (iv), ie, after filtration.

Detailed description of the invention In the method of the present invention as summarized above, kasugamycin of various degrees of purity can be reacted, preferably in the presence of an acid catalyst, with an acetylating agent under conditions that favor the acetoysis of the aminoglycoside. Ideally, kasugamycin is in the form of a hydrochloride salt; however, the term "kasugamycin" refers to both the kasugamycin base as well as any acid or base addition salt that is readily available and is suitable for use as described hereinbefore. In a favored embodiment of the invention, the acetylating agent is selected from acetic anhydride, a mixture of acetic anhydride and acetic acid, trifluoroacetic anhydride and, a mixture of trifluoroacetic anhydride and trifluoroacetic acid and, a mixture of acetyl halide and acetic acid; a mixture of acetic anhydride and acetic acid in a ratio (by volume) of about 1: 1 is preferred. The acid catalyst, on the other hand, can be selected from mineral acids and Lewis acids. Suitable mineral acids include hydrochloric acid, hydrobromic acid, hydrofluoric acid, nitric acid, sulfuric acid and perchloric acid; Suitable Lewis acids include BF3-etherate and FeCI3. Preferred acid catalysts include concentrated sulfuric acid and 70% perchloric acid, of which 10 drops are sufficient per 100 mL of total reaction volume. Acid-functionalized resins including, but not limited to, I R-120 and A-15 (Aldrich Chemical Co., Milwaukee, Wl) are also preferred. Especially preferred acid-functionalized resins include resin-supported sulfonic acids. The reaction of acellisis can be carried out during a period that depends on the temperature and the choice of reagents; The required time can vary from two hours to three days and, the temperature can vary from the environmental up to 120 ° C. The product of the acetolysis reaction is hexa-O-acetyl-Do / u / ro-inositol or, in the case that trifluoroacetic anhydride is used as the acetylating agent, hexa-O-trifluoroacetyl-D-qu / ro-inositol. It is intended, both in the specification and in the claims thereof, that the term "hexa-acetate" encompass both the hexa-O-acetyl and hexa-O-trifluoroacetyl intermediates. After acetolysis, the crude hexa-acetate can be purified as described above starting with the removal of the acetylating agent, preferably by vacuum evaporation as in a rotary evaporator, typically resulting in the formation of an oily residue. Once "stripped" of substantially all of the acetylating agent, the residue can then be diluted in a solvent system which ideally comprises a first polar solvent. Polar solvents that may be used include, but are not intended to be limited to, acetone, methanol, ethanol, ethyl acetate, CH3CN, CH2Cl2, CHCl3, and 1,2-dichloroethane. This solvent system may optionally also comprise a second non-polar solvent selected from long-chain hydrocarbons and aromatic hydrocarbons, especially pentane, hexane, heptane, benzene, xylene or toluene. A system comprising a first polar solvent and a second non-polar solvent in a ratio (by volume) ranging from 1: 1 to about 10: 1 is preferred. A system comprising ethyl acetate and hexane in a ratio (by volume) ranging from about 1: 1 to about 10: 1 is especially preferred. In accordance with one embodiment of the invention, the resulting solution of the crude hexa-acetate is then passed through a filter material which retains any solids as well as some of the by-products contaminating the aceto-synthesis reaction. Depending on the selection of the solvent system, suitable filter materials may include silica gel, alumina, activated carbon, diatomaceous earth and a mixture of alumina and diatomaceous earth.; silica gel is preferred for use with the above ethyl acetate / hexane system. The residual acids in the solution of the purified hexa-acetase can then be neutralized; in particular by washing the solution with a water-based solution. Preferred aqueous base solutions include, but are not intended to be limited to, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate. More preferably, the water-based solutions used are sodium bicarbonate and sodium bicarbonate. In addition, the cold, aqueous based solutions above can be used to neutralize the acids. (Alternatively, the neutralization step can be carried out before purification, by washing the crude hexa-acetate solution before filtration). After separation of the organic (intermediate containing) and aqueous (for example, bicarbonate-containing layers), the purified hexa-acetate solution is stripped again of the solvent, typically resulting as before in the formation of an oil containing the intermediate In the event that the acetylating agent (such as acetic anhydride) or water (from the previous neutralization, for example, with sodium bicarbonate solution) remains in the purified hexa-acetate, an optional "azo-drying" step In said step, the purified intermediate was dissolved in a suitable solvent, such as toluene, isopropanol or n-propanol.The solvent is then separated or evaporated, together with any azeotropes formed by the solvent and the above contaminants, leaving a more highly purified hexa-acetate material In accordance with even another embodiment of the invention, it can execute is a method for the purification of the product of the acetolysis in the following manner. The crude hexa-acetate mixture can be concentrated by vacuum distillation to remove the acetic acid while retaining the excess acetic anhydride. The mixture can then be diluted with cold diluted aqueous base. Suitable bases for this purpose include, but are not intended to be limited to, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate. The diluted aqueous base neutralizes the residual acid catalysts (when the acid-functionalized resins are used as the catalyst, then the crude hexa-acetate mixture is filtered, concentrated and then diluted with water). The product obtained after the neutralization step is extracted into a mixture of ethyl acetate and heptane or toluene. The organic components combined either only with water or with a water-based solution (for example, bicarbonate solution) and then followed by water. The solution can be concentrated to an oil by vacuum distillation (e.g., rotary evaporation) and then azeo-dried using a solvent system described above to produce a purified hexa-acetate. Optionally, the purified hexa-acetate can be further purified by crystallization. The pure hexa-acetate oil is dissolved in a solvent with heat and allowed to cool. Solvents that may be used include, but are not intended to be limited to, 1-butanol, 2-butanol, 1-propanol, 2-propanol, ethanol, methanol or aqueous solutions of the above solvents.

The deacetylation (or saponification) of the purified hexa-acetate can then be carried out, for example under basic conditions such as those described in Chem. Ber. 56: 1705 (1923) and J. Chem .Soc. 3166 (1960). In particular, deacetylation can be achieved by dissolving the hexa-acetate in methanol and adding a basic catalyst selected from lithium methoxide, sodium methoxide, barium methoxide and potassium methoxide, with sodium methoxide being preferred. (Alternatively, the catalyst can be added to the solvent before the hexa-acetate). The amount of catalyst can vary from about 0.01 to 0.05 molar equivalents (or more, if significant amounts of the acetylating agent remain). The reaction can be initiated at room temperature, resulting in the precipitation of the intermediate of the product of D-q u / ro-inositol and, it can then be continued by heating to reflux for up to 12 hours. Upon cooling, the product can be easily isolated by filtration and drying. Other possible means for the deacetylation of hexa acetate include reacting the intermediate with suitable amounts of solvent with an acid as described in Che. Ber. 92: 173 (1959). For example, the intermediate can be reacted with methanol or ethanol and hydrochloric acid or sulfuric acid. Preferably, methanol and sulfuric acid are used. Additional deacetylation procedures that can be employed are described in H. S. Khadem, Carbohydrate Chemistry: Monosaccharides and Their Oligomers, Academic Press (San Diego, 1988) (decomposition of acetate esters using sodium hydroxide in acetone) and T. W. Greene and P.M. M. -Wuts, Protective Groups in Organic Synthesis, Wiley & Sons (New York, 1991), pp. 90 and 418-420 (identifying several reagents and possible conditions). Although the above methods result in a D-qu / 'ro-inositol product of considerable purity, it may be desired to further purify the product by recrystallization. In one embodiment of said purification step, the product is dissolved in a suitable solvent such as water, after which the crystallization is induced (as for example by the addition of methanol and / or ethanol) and the solid product is collected by conventional means. Likewise, if the discoloration of the product is necessary, D-u-inositol can be treated with activated carbon while it is in solution. As used in this specification and the appended claims, the following terms have the specified meanings: The term "aromatic hydrocarbons" as used herein refers to cyclic unsaturated hydrocarbons having from six to ten carbon atoms including, although they are not limited to, benzene, xylene and toluene. The term "long chain hydrocarbons" as used herein refers to straight or branched chain saturated hydrocarbons of between five and ten carbon atoms including, but not limited to, pentane, hexane and heptane. The method of the present invention will be better understood in relation to the following examples, which are intended to be illustrative and not limiting of the scope of the invention. Within and through the specification, it is intended that citations to literature be expressly incorporated by reference.

Example 1 Preparation of hexa-O-acetyl-D-qu ro-inositol from kasugamycin In a process representative of the method of the present invention, the hexa-O-acetyl-D-qru / ro-inositol intermediate was prepared according to the following procedure: Kasugamycin hydrochloride was heated at 100 ° C under nitrogen for 24 hours. 0.98 g, 2.36 millimoles (mmol), Sigma Chemical Co., St. Louis) in 10 mL of acetic anhydride, 10 mL of acetic acid and 2 drops of concentrated sulfuric acid. After being cooled, the brown color mixture was concentrated by rotary evaporation (maximum bath temperature, 65-70 ° C) to a brown oil. This oil was diluted with 100 mL of a 1: 1 (by volume) mixture of mixed ethyl acetate and hexanes and heated to reflux for 1 hour. The result was a solution of medium amber color, clear with brown solids. After cooling to room temperature, this mixture was filtered through a short plug (about 20 g) of silica gel which had been moistened with ethyl acetate / hexanes at 1: 1. The silica filter material was washed with 300 mL of ethyl acetate / hexanes at 1: 1. The collected organic fractions were combined and concentrated by rotary evaporation to an amber oil which was found to move easily on a silica gel thin layer chromatography plate (Rf = 0.27 using ethyl acetate / hexanes 1: 1) and they could be visualized with phosphomolybdic acid after heating for 1 or 2 minutes. Based on the similarity of these results with the data reported for hexa-O-acetyl-m / 'o-inositol, the product was identified as hexa-O-acetyl-D-qu ro-inositol.

Example 2 Physical characterization of hexa-O-acetyl-D-qt // ro-inositol The material prepared in the above manner was further purified by chromatography using ethyl acetate / hexanes at 1: 1 and concentrated to a pale amber oil. Removal of the residual solvent in a vacuum oven at 65 ° C overnight gave 61% an oil that had a spectrum? N MR consistent with that of the desired product. Due to an axis of rotational symmetry, only three acetate signals are present in the proton spectrum and a relatively simple pattern of signals was observed. ? NMR (300 Mhz, CDCl 3): 51 .99 (s, 6H); 2.04 (s, 6 H); 2.19 (s, 6H); 5.29 (dt, 2H); 5.38 (D, 2H); 5.42 (dd, 2H).

Example 3 Preparation of hexa-O-acetyl-D-qu / ro-inositol from kasugamycin In an alternative embodiment of the method of the present invention, kasugamycin (1 .00 g) in 5 mL of acetic anhydride, 5 mL of acetic acid and 0.26 mL of concentrated sulfuric acid were heated at 100 ° C under nitrogen for 24 hours. The dark brown mixture was cooled to room temperature and concentrated by rotary evaporation to an oil. This residue was slurried in 25 ml of a 3: 2 (by volume) mixture of ethyl acetate and heptanes for 20 minutes and then filtered through 2 g of silica gel which had been moistened with ethyl acetate. . The filter material was washed with 15 mL of ethyl acetate / hexanes at 3: 2 and the collected organic fractions were combined. These were then washed with saturated aqueous sodium bicarbonate (4 x 50 mL), water (1 x 50 mL) and brine (1 x 50 mL) and dried over sodium sulfate. The resulting material was filtered through a thick concreted glass funnel and concentrated to an oil by rotary evaporation. This oil was after-dried by dissolving in 20 mL of toluene and reconcentrating using a rotary evaporator. The 0.95 g of pale amber oil was identified by TLC as the hexa-acetate intermediate.

Example 4 Conversion of hexa-O-acetyl-D-qt // ro-inositol to D-qa / ro-inositol The hexa acetate product of Example 3 (0.83 g) was dissolved in 10 mL of methanol. Three drops of 25% NaOMe / MeOH were added to the stirred solution which was then heated to reflux for 15 hours. The pulp was cooled to room temperature and the solids were collected by filtration. The collected solids were then washed with ethanol at room temperature (approximately 5 mL) and dried to constant weight in a vacuum oven at 75 ° C, obtaining D-qu / ro-inositol (0.28 g, 80% yield) by | H NMR was > 98% pure.

Example 5 Preparation of hexa-O-acetyl-D-qt // ro-inositol to remove kasugamycin 90 mg of Kasugamycin (120 g) (Kaken Pharmaceuticals Ltd., Tokoyo, Japan) were heated at 90 ° C under nitrogen for 15 hours in 275 g of acetic anhydride and 12 g of sulfuric acid. The mixture was concentrated by rotary evaporation to a net weight of 332 g, then cooled to room temperature. The concentrated reaction mixture was partitioned between 350 μL of water, which had been cooled to 5 ° C and 350 mL of ethyl acetate / heptane (5: 1 volume / volume). The combined organics were washed with three portions of 200 mL of water, then concentrated by rotary evaporation. The resulting oil was diluted with toluene (154 g) and concentrated leaving an oil (17 g). The oil residue was dissolved in isopropanol (80 g) and concentrated to an oil (12 g). The hexa acetate was recrystallized by dissolving the residual oil in warm isopropanol (120 g) (65 ° C). After stirring the cooled solution overnight, the solids were collected, obtaining the purified hexa-acetate (92 g). An additional recrystallization from 40% aqueous methanol (142 g) yielded 75 g of hexa acetate which had > 99.5% as determined by Gas Chromatography (GC).

Example 6 Conversion of hexa-O-acetyl-D-qu ro-inositol The hexa acetate from Example 5 was heated at 55 ° C in methanol (150 g) and hydrochloric acid (2.5 g) for 15 hours. After being cooled to 5 ° C for one hour, the solids were collected (27.8 9) - The D-qiv / 'ro-inositol was dissolved in water (83 g), heated with activated carbon at 65-75 ° C for one hour, filtered and concentrated to a net weight of 56 g by evaporation rotating The solution was heated to 75 ° C, then diluted with ethanol maintaining a solution temperature higher than 65 ° C. After stirring the cooled solution overnight, the solids were collected and dried 24.8 g. Further recrystallization from water (30 g) and ethanol (149 g) yielded 24.0 g of D-chiro-inositol which had > 99.8% purity as determined by high performance liquid chromatography (HPLC). It is understood that the foregoing detailed description and the accompanying examples are merely illustrative and are not considered limitations on the scope of the invention, which is defined only by the appended claims and their equivalents. Various changes and modifications for the described modifications will be apparent to those with experience in the art. Such changes and modifications, including without limitation those relating to the reagents, concentrations and reaction conditions used in the method of the invention, can be made without departing from the spirit and scope thereof.

Claims

1. A method for the preparation of D-gu / ro-inositol from kasugamycin, comprising (a) reacting kasugamycin with an acetylating agent to form a crude hexa-acetate; (b) purifying the crude hexa-acetate to form a purified hexa-acetate; (c) deacetylating the purified hexa-acetate to form D-chiro-inositol; and (d) isolate D-qu / ro-inositol.

2. A method according to claim 1, wherein the reaction in step (a) is carried out in the presence of an acid catalyst.

3. A method according to claim 2, wherein the acetylating agent is selected from the group consisting of acetic anhydride, a mixture of acetic anhydride and acetic acid, trifluoroacetic anhydride, a mixture of trifluoroacetic anhydride and trifluoroacetic acid and , a mixture of acetyl halide and acetic acid.

4. A method according to claim 3, wherein the acetylating agent is a mixture of acetic anhydride and acetic acid in a ratio ranging from about 1: 1 to 10: 1.

5. A method according to claim 2, wherein the acid catalyst is selected from the group comprising mineral acids and Lewis acids.

6. A method according to claim 5, wherein the acid mineral is selected from the group comprising hydrochloric acid, hydrobromic acid, hydrofluoric acid, nitric acid, sulfuric acid and perchloric acid.

7. A method according to claim 2, wherein the acid catalyst is an acid functionalized resin.

8. A method according to claim 7, wherein the acid catalyst is a sulphonic acid supported by resin.

9. A method according to claim 5, wherein the Lewis acid is selected from the group comprising BF3-etherate and FeCI3.

10. A method according to claim 2, wherein the acid catalyst is selected from the group comprising sulfuric acid and perchloric acid.

A method according to claim 1, wherein the purification in step (b) comprises the sub-steps of: (i) substantially removing the acetylating agent to form a residue; (ii) dilute the residue in a suitable solvent system to form a crude hexa-acetate solution; (iii) filtering the solution of hexa-O-acetyl-D-qw ro-inositol to form a solution of purified hexa-acetate; and (iv) substantially remove the solvent.

12. A method according to claim 11, wherein the removal of the acetylating agent in the sub-step (i) is carried out by vacuum evaporation of the acetylating agent.

13. A method according to claim 11, wherein the solvent system in the sub-step (i) comprises a first polar solvent is selected from the group comprising acetone, methanol, ethanol, ethyl acetate, CH3CN, CH2Cl2, CHCl3 and 1,2-dichloroethane.

A method according to claim 11, wherein the solvent system additionally comprises a second non-polar solvent selected from the group comprising long-chain hydrocarbons and aromatic hydrocarbons.

15. A method according to claim 14, wherein the second non-polar solvent is selected from the group comprising pentane, hexane, heptane, benzene, xylene and toluene.

A method according to claim 15, wherein the solvent system is a mixture of ethyl acetate and hexane or toluene in a ratio of about 1: 1.

17. A method according to claim 11, wherein the filtration in sub-step (iii) comprises passing the crude hexa-acetate solution through a filter material selected from the group comprising silica gel, alumina, activated carbon, diatomaceous earth and a mixture of alumina and diatomaceous earth.

18. A method according to claim 17, wherein the filter material is silica gel.

19. A method according to claim 11, which comprises the additional sub-step, between the sub-steps (ii) and (iii), of neutralizing the crude hexa-acetate solution.

20. A method according to claim 19, wherein the neutralization is carried out by washing the crude hexa-acetate solution with an aqueous base solution.

21. A method according to claim 20, wherein the aqueous base solution is selected from the group comprising sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.

22. A method according to claim 11, comprising the additional sub-step, between the sub-steps (iii) and (iv), of neutralizing the purified hexa-acetate solution.

23. A method according to claim 22, wherein the neutralization is carried out by washing the purified hexa-acetate solution with aqueous base solution.

24. A method according to claim 23, wherein the aqueous base solution is selected from the group comprising sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.

25. A method according to claim 11, comprising the additional sub-step, after sub-step (iv), of aze-drying the purified hexa-acetate.

26. A method according to claim 25, wherein the azeo-drying is carried out using a solvent selected from the group comprising toluene, isopropanol and n-propanol.

27. A method according to claim 11, wherein the deacetylation in step (c) is carried out by dissolving the hexa-acetate in a solvent selected from the group comprising methanol and ethanol and adding a sufficient amount of a basic catalyst selected from the group comprising lithium methoxide, sodium methoxide, barium methoxide and potassium methoxide to produce deacetylation.

28. A method according to claim 11, wherein the basic catalyst is sodium methoxide.

29. A method according to claim 1, wherein the deacetylation in step (c) is carried out by reacting the hexa-acetate with a solvent and an acid.

30. A method according to claim 29, wherein the solvent is selected from the group comprising methanol and ethanol.

31. A method according to claim 29, wherein the acid is selected from the group comprising hydrochloric acid or sulfuric acid.

32. A method according to claim 29, wherein the deacetylation in step (c) is carried out by reacting the hexa-acetate with a methanol and sulfuric acid.

33. A method according to claim 29, wherein the solvent is selected from the group comprising methanol and ethanol.

34. A method according to claim 29, wherein the acid is selected from the group comprising hydrochloric acid or sulfuric acid.

35. A method according to claim 1, comprising the additional step, after isolation in step (d), of purifying D-qu / ro-inositol by recrystallization.

36. A method according to claim 35, wherein the recrystallization of D-qtv / ro-inositol comprises the sub-steps: (i) dissolving the D-qi / 'ro-inositol in water; and (ii) precipitating the D-qw ro-inositol from the solution.

37. A method for the preparation of D-qu ro-inositol from kasugamycin, comprising: (a) reacting kasugamycin with an acetylating agent to form a mixture of crude hexa-acetate; (b) concentrating the crude hexa-acetate mixture; (c) extracting the crude hexa-acetate product with a solvent system; (d) washing the crude hexa-acetate with water; (e) concentrating the crude hexa-acetate solution to form a purified hexa-acetate; (f) deacetylating the purified hexa-acetate to form D-chiro-inositol; and (g) isolate D-qw / ro-inositol.

38. A method according to claim 37, wherein the crude hexa-acetate was concentrated by vacuum distillation.

39. A method according to claim 37, wherein the crude hexa-acetate is neutralized after extraction with a solvent system.

40. A method according to claim 39, wherein the neutralization is carried out by washing the concentrated crude hexa-acetate solution with aqueous base solution.

41. A method according to claim 40, wherein the aqueous base solution is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate. .

42. A method according to claim 39, wherein the neutralization is carried out after forming a purified hexa-acetate.

43. A method according to claim 42, wherein the neutralization is effected by washing the solution of the purified hexa-acetate with aqueous base solution.

44. A method according to claim 43, wherein the aqueous base solution is selected from the group comprising sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.

45. A method according to claim 37, wherein the solvent system comprises a first polar solvent that is selected from the group comprising ethyl acetate, CH3CN, CH2Cl2, CHCl3, and 1,2-dichloroethane.

46. A method according to claim 37, wherein the solvent system further comprises a second non-polar solvent selected from the group comprising long-chain hydrocarbons and aromatic hydrocarbons.

47. A method according to claim 46, wherein the second non-polar solvent is selected from the group comprising pentane, hexane, heptane, benzene, xylene and toluene.

48. A method according to claim 37, wherein the solvent system is a mixture of ethyl acetate and hexane or toluene in a ratio of from about 1: 1 to about 10: 1.

49. A method according to claim 37, wherein sub-step (d) comprises washing the crude hexa-acetate product first with an aqueous-based solution and then followed by water.

50. A method according to claim 49, wherein the aqueous base solution is bicarbonate solution.

51. A method according to claim 37, wherein the crude hexa-acetate is concentrated by azeo-drying.

52. A method according to claim 51, wherein the azeo-drying is carried out using a solvent selected from the group comprising toluene, isopropanol and n-propanol.

53. A method according to claim 37, wherein the purified hexa-acetate is further purified by dissolving the pure hexa-acetate in a solvent with heat and then allowing to cool.

54. A method according to claim 53, wherein the solvent is selected from the group comprising: 1-butanol, 2-butanol, 1-propanol, 2-propanol, ethanol, methanol or aqueous solutions of the above solvents .

55. A method according to claim 37, wherein the D-qu ro-inositol is further purified by recrystallization.

56. A method according to claim 55, wherein the recrystallization of D-qu / ro-inositol comprises the sub-steps of: (i) dissolving the D-qu ro-inositol in water; and (ii) precipitating the D-qu / ro-inositol from the solution.

57. A method according to claim 56, wherein the D-qtv ro-inositol is neutralized with a basic resin before precipitation.

58. A method according to claim 37, wherein the deacetylation step is carried out by reacting the hexa-acetate with a solvent and an acid.

59. A method according to claim 58, wherein the solvent is selected from the group comprising methanol and ethanol.

60. A method according to claim 58, wherein the acid is selected from the group comprising hydrochloric acid or sulfuric acid.

61. A method according to claim 58, wherein the deacetylation step is carried out by reacting the hexa-acetate with methanol and sulfuric acid.