A process for the purification of voglibose is provided. Also, processes for the purification of substituted or unsubstituted 5-oxo-1,2,3,4-cyclohexanetetrol, and substituted 5-amino-1,2,3,4-cyclohexanetetrol, which are useful intermediates in the preparation of voglibose are provided.
Chemically, voglibose is (1S)-(1(OH),2,4,5/1,3)-5-[[2-hydroxy-1-(hydroxymethyl) ethyl]amino]-1-C-(hydroxymethyl)-1,2,3,4-cyclohexanetetrol, which has an excellent inhibitory activity against glucoside hydrolase. Several processes have been reported for the preparation of voglibose such as US 4,701,559; US 4,824,943; US 4,898,986; US 6,150,568; J. Org. Chem., 1992, 57, 3651; and J. Med. Chem., 1986, 29, 1038.
All the above references report the use of ion-exchange chromatography with water as eluent, followed by concentration of the aqueous solution and recrystallization from ethanol to obtain pure voglibose. This is a difficult procedure unsuitable at commercial scale, since it involves recovery of large amounts of water requiring prolonged heating and results in a low overall yield of the product. The product, obtained by the reported processes, is initially hygroscopic and often converts to sticky oil when exposed to atmosphere. In light of the above, an improved process to avoid chromatographic technique for the purification of voglibose, which minimizes or eliminates the above problems and is convenient to operate on a commercial scale, is required.
Purification of (1 S)-(1 (OH),2,4,5/1,3)-5-amino-1 -C-(hydroxymethyl)-1,2,3,4-
cyclohexanetetrol (valiolamine) by ion-exchange chromatographic method has been reported in several references such as US 4,701,559 and US 4,824,943. Purification of (1 S)-(1 (OH),2,4,5/1,3)2,3,4-tri-O-benzyl-5-amino-1 -C-[(benzyloxy)methyl]-1,2,3,4-cyclohexanetetrol (tetra-O-benzylvaliolamine) by chromatography on silica gel using chloroform and methanol as eluent is disclosed in J. Org. Chem., 1992, 57, 3651.
US 4,824,943 discloses purification of (1S)-(1(OH),2,4/1,3)-2,3,4-tri-O-benzoyl-1-C-(benzoyloxymethyl)-5-oxo-1,2,3,4-cyclohexanetetrol (tetra-O-benzoylvaliolone) by using column chromatography on silica gel with toluene and ethyl acetate. US 4,898,986; and

J. Org. Chem., 1992, 57, 3642 disclose purification of (1S)-(1(OH),2,4, /1,3)-2,3,4-tri-O-benzyl-1-C-(benzyloxymethyl)-5-oxo-1,2,3,4-cyclohexanetetrol(tetra-O-benzylvaliolone) by using column chromatography on silica gel with toluene and ethyl acetate followed by treatment with a mixture of ethyl ether and petroleum ether. Ion exchange column chromatography is used for the purification of (1S)-(1(OH),2,4/1,3)- 1-C-(hydroxy methyl)- 5-oxo-1,2,3,4-cyclohexanetetrol (valiolone) in US patent No. 6,150,568.
In one aspect, a process for the purification of voglibose, comprising providing a solution of crude voglibose in methanol and recovering pure voglibose, is provided.
In another aspect, a process for the purification of compound of formula I, as shown in the accompanied drawings, wherein R is a protecting group, comprising contacting crude compound of formula I with an ether and recovering pure compound of formula I, is provided.
In yet another aspect, a process for purification of compound of formula II, as shown in the accompanied drawings, wherein R' is hydrogen or any protecting group, comprising dissolving crude compound of formula II in a solvent selected from the group consisting of alcohols, ketones, and mixtures thereof and recovering pure compound of formula II, is provided.
The solution of "crude voglibose " may be obtained by dissolving crude voglibose obtained from any of the synthetic routes described in the prior art, including those described in US 4,701,559; US 4,824,943; US 4,898,986; US 6,150,568; J. Org. Chem., 1992, 57, 3651; and J. Med. Chem., 1986, 29, 1038, in methanol at room temperature, or at higher temperatures up to reflux temperatures. The solution may also be obtained directly from a reaction mixture of the last step of a process in which voglibose is prepared, and used as such in the process. In case, the solvent of such a solution is not methanol, the undesired solvent may be replaced by methanol by conventional methods known in art. Crude voglibose may contain corresponding anti-isomers, polymeric

impurities or any other impurity, which may arise during production or storage, such as degradation products.
The solution of voglibose in methanol may be treated with carbon in some particular embodiments.
Recovery of pure voglibose may be accomplished by concentration, crystallization, precipitation, cooling or a combination thereof followed by separation and drying.
Precipitation may occur on addition of an antisolvent, i.e. a solvent in which voglibose is insoluble or sparingly soluble, to the methanol solution. Alternatively, precipitation can be induced by concentration and/or reducing the temperature of methanol solution, especially if the initial temperature is elevated.
Examples of antisolvent that may be added to precipitate out pure voglibose include hydrocarbons such as hexane, cyclohexane, toluene, heptane and octane; lower alkyl ethers such as diethylether and diisopropylether; ketones such as acetone and methyl isobutyl ketone; esters such as ethylacetate and isopropylacetate; and mixtures thereof.
The crystallization time and temperature is not critical for example, the crystallization may be performed at temperatures of from about 10° C to about 40° C for 30 minutes to 2 hours in some particular embodiments.
The separation of pure voglibose may be accomplished by decanting, filtering, centrifuging and similar processing methods for separating solids from liquids known in the art, or any combination of these separation methods.
Examples of protecting groups in the compound of formula I and formula II, as shown in the accompanied drawings, include optionally substituted Ci_6 straight or branched chain alkyl, optionally substituted benzyl and benzoyl groups. Examples of alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary and tertiary butyl. The substituted

benzyl groups include p-nitro benzyl, p-methoxy benzyl, o-nitro benzyl, p-bromo benzyl and 2,4,6, trimethyl benzyl.
Crude compound of formula I may be obtained from any of the synthetic routes described in the prior art, including those described in US 4,824,943; US 6,150,568; and J. Org. Chem., 1992, 57, 3651. It may also be obtained as a solution directly from a reaction mixture of the last step of a process in which it is prepared and used as such in the process.
Examples of ether, used in the purification of compound of formula I, include diethyl ether, diisopropyl ether, tert-butylethyl ether, tert-butylmethyl ether and mixtures thereof.
The term "contacting" includes slurrying, stirring, triturating or a combination thereof.
The crude compound of formula I may be stirred in ether at about 40° C to about 60° C in some particular embodiments.
Recovery of the pure compound of formula I may be accomplished by concentration, cooling, decanting, layer separation, filtration or a combination thereof followed by drying.
Crude compound of formula II may be obtained from any of the synthetic routes described in the prior art, including those described in US 4,701,559; US 4,824,943; US 4,898,986 and J. Org. Chem., 1992, 57, 3642. It may also be obtained as a solution directly from a reaction mixture of the last step of a process in which it is prepared and used as such in the process.
Examples of alcohols include methanol, ethanol, isopropanol and mixtures thereof. Examples of ketones include acetone , methyl isobutyl ketone mixtures thereof.

Crude compound of formula II may be dissolved in alcohol or ketone at about 40° C to reflux temperature in some particular embodiments.
Recovery of the pure compound of formula II may be accomplished by concentration, crystallization, cooling or a combination thereof followed by separation and drying.
The crystallization time and temperature is not critical for example the crystallization may be performed by stirring at temperatures of from about 10° C to about 40° C for 30 minutes to 3 hours in some particular embodiments.
The separation of pure compound of formula II may be accomplished by decanting, filtering, centrifuging and similar processing methods for separating solids from liquids known in the art, or any combination of these separation methods
In the following section embodiments are described by way of examples to illustrate the process of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of this examples would be evident to persons ordinarily skilled in the art.
EXAMPLE-1
Preparation of pure (1S)-(1(OH),2,4,5/1,3)-5-[[2-hydroxy-1-(hydroxymethyl) ethyl]amino]-1 -C-(hydroxymethyl)-1,2,3,4-cyclohexanetetrol (voglibose):
Crude (1S)-(1(OH),2,4,5/1,3)-5-[[2-hydroxy-1-(hydroxymethyl) ethyl]amino]-1-C-(hydroxymethyl)-i ,2,3,4-cyclohexanetetrol (voglibose, 109 g, HPLC purity: 97.5%) was dissolved in methanol (6.6 I) at reflux temperature. Charcoal (4 g) was then added to the above solution at 50°C and stirred for 30 minutes at the same temperature. The reaction mixture was filtered through hyflo bed and hyflo bed was washed with methanol (500 ml). Methanol (about 6 I) was distilled out and the concentrated solution was stirred at

25-30°C for 1 hour. The obtained solid was filtered and washed with methanol. The
product was dried at 45-50° C under reduced pressure to get the title compound as
white crystals.
Yield: 99 g
HPLC Purity: 99.6%
EXAMPLE-2
Synthesis of pure (1S)-(1(OH),2,4,5/1,3)-2,3,4-tri-O-benzyl-5-amino-1-C-[benzyloxymethyl]-1,2,3,4-cyclohexanetetrol (tetra-O-benzyl valiolamine):
To a solution of pure (1S)-(1(OH),2,4 /1,3)-2,3,4-tri-O-benzyl-1-C- (benzyloxymethyl)- 5-oxo-1,2,3,4-cyclohexanetetrol (tetra-O-benzylvaliolone, 50 g, 0.09 mol) in methanol (500 ml) were added ammonium acetate (75 g, 0.97 mol) and sodium cyanoborohydride (20 g, 0.318 mol). The mixture was stirred overnight at 30 - 35° C. The solvent was distilled off under reduced pressure and water (250 ml) was then added into the reaction mixture followed by extraction with ethyl acetate (250 ml). The organic layer was washed with water followed by brine solution, and concentrated to give tetra-O-benzyl valiolamine as colorless syrup (HPLC purity: 74.7%). The syrup was stirred with diisopropylether (100 ml) at 45 - 50°C for 30 minutes. The lower thick layer of tetra-O-benzylvaliolamine was separated. The process was repeated with diisopropylether (100 ml). The separated lower layer was then concentrated to dryness to give colorless foamy solid of pure tetra-O-benzyl valiolamine. Yield: 99g HPLC Purity: 88.1%

EXAMPLE-3
Purification of (1S)-(1(OH),2,4/1,3)-2,3,4-tri-O-benzyl-1-C- (benzyloxymethyl)- 5-oxo-1, 2,3,4-cyclohexanetetro! (tetra-O-benzylvaliolone):
Crude (1S)-(1(OH),2,4/1,3)-2,3,4-tri-O-benzyl-1-C- (benzyloxymethyl)- 5-oxo-1,2,3,4-
cyclohexanetetrol (tetra-O-benzylvaliolone, 140 g, HPLC purity: 78.5%) was dissolved in
methanol (700 ml) at 45 - 50° C and the mixture was cooled to 20 - 25° C. The mixture
was stirred for 2 hours at the same temperature. The precipitated solid was filtered and
washed with methanol. It was then dried at 35 to 40° C under reduced pressure to get
the pure title compound.
Yield: 95g
HPLC Purity: 94.7%
M.P.:98-99°C