Background of the Invention Chemically, voglibose is (IS)- (1 (OH), 2,4, 5/1, 3)-5- [ [2-hydroxy-l- (hydroxymethyl) ethyl] amino]-1-C- (hydroxymethyl)-1, 2,3, 4-cyclohexanetetrol, and has been disclosed as being an excellent inhibitory activity against glucoside hydrolase. Several processes have been reported for the preparation of voglibose such as in U. S. Patent Nos. 4,701, 559, 4,824, 943,4, 898,986, 6,150, 568; J. Org. Chem., 57: 3651 (1992) and J. Med. Chem., 29: 1038 (1986).

Valiolamine, which is chemically known as (lS)- (l (OH), 2,4, 5/1, 3)-5-amino-1- hydroxymethyl-1, 2,3, 4-cyclohexanetetrol, has been disclosed as having a-glucosidase inhibitory activity and is a key intermediate for the preparation of voglibose. It has been prepared by synthetic and fermentation procedures disclosed in U. S. Patent Nos.

4,827, 036 and 4,446, 319; and Carbohydr. Res., 140: 180 (1985).

U. S. Patent No. 4,824, 943 and J Org. Chem., 57: 3651 (1992) disclose a process <BR> <BR> <BR> <BR> for the preparation of valiolamine comprising reacting (lS)- (l (OH), 2, 4/1, 3) -2,3, 4-tri-0- benzyl-5-oxo-l-C- [benzyloxymethyl]-1, 2,3, 4-cyclohexanetetrol with hydroxylamine <BR> <BR> <BR> <BR> hydrochloride to obtain (IS)- (1 (OH), 2,4, 5/1, 3) -2,3, 4-tri-O-benzyl-5-(hydroxyimino)-1-C- [benzyloxymethyl]-1, 2,3, 4-cyclohexanetetrol followed by reduction to yield (1S)- (1 (OH), 2,4, 5/1, 3) -2,3, 4-tri-O-benzyl-5-amino-1-C-[benzyloxymethyl]-1, 2,3, 4- cyclohexanetetrol, which was further reduced to (lS)- (l (OH), 2,4, 5/1, 3)-5-amino-1- hydroxymethyl-1, 2,3, 4-cyclohexanetetrol in the presence of a metal catalyst.

U. S. Patent No. 4,898, 986 discloses dechlorination of (lS)-(l (OH), 2, 4/1, 3) -2,3, 4- tri-O-benzyl-6, 6-dichloro-5-oxo-1-C-[benzyloxymethyl]-1, 2,3, 4-cyclohexanetetrol in the presence of palladium-barium sulfate and sodium acetate at a pressure of 3 to 3.5 kg/cm.

However, there remains a need for new processes in preparing 1,2, 3,4- cyclohexanetetrol derivatives.

Summary of the Invention Provided herein are processes for preparing compounds of Formula I,

Formula I and pharmaceutical acceptable salts thereof, comprising reacting a compound of Formula II,

Formula 11 with ammonium acetate, ammonium formate or a mixture thereof and one or more reducing agent, wherein R can be a hydrogen atom or a hydroxyl protecting group. The reducing agent can be one or more of an alkali metal borohydride, an alkali metal aluminum hydride, an alkali metal cyanoborohydride, a metal catalyst in the presence of hydrogen, a dialkyl amine borane or mixtures thereof. The alkali metal borohydride can be, for example, sodium borohydride, potassium borohydride, lithium borohydride, sodium trimethoxyborohydride or mixtures thereof ; the alkali metal aluminum hydride can be, for example, lithium aluminum hydride, sodium aluminum hydride or mixtures

thereof; the alkali metal cyanoborohydride can be, for example, sodium cyanoborohydride; the metal catalyst can be, for example, palladium-carbon, palladium black, Raney-nickel, platinum black, platinum dioxide, rhodium carbon or mixtures thereof ; and the dialkyl amine borane can be, for example, dimethylamine borane.

The hydroxyl-protecting group can be an acyl-type protecting group, an acetal-or ketal-type protecting group, or an ether-type protecting group. The acyl-type protecting group can be, for example, an optionally substituted alkanoyl, benzoyl, alkoxycarbonyl, alkenyloxycarbonyl, benzyloxycarbonyl or phenyloxycarbonyl group; the acetal-or ketal- type protecting group can be, for example, methylene, ethylene, isopropylidene or butylidene groups; and the ether-type protecting group can be, for example, an alkyl, alkenyl or benzyl group.

The reaction can be carried out in the presence of one or more solvent that is inert under reaction conditions. Such solvents can be, for example, water, an alcohol, an ether, a chlorinated hydrocarbon, an ester, a nitrile, a ketone, a dipolar aprotic solvent, a cyclic ether or mixtures thereof.

The one or more reducing agent can be added simultaneously with ammonium acetate or ammonium formate or the one or more reducing agent can be added after the reaction of the compound of Formula II with ammonium acetate or ammonium formate.

In another aspect, the compound of Formula II can be prepared by dehalogenation of the compound of Formula III, Formula III wherein R can be a hydrogen atom or a hydroxyl protecting group and X can be halogen, for example, chlorine, bromine or iodine. The hydroxyl-protecting group can be an acyl- type protecting group, an acetal-or ketal-type protecting group, or an ether-type protecting group. The acyl-type protecting group can be, for example, an optionally substituted alkanoyl, benzoyl, alkoxycarbonyl, alkenyloxycarbonyl, benzyloxycarbonyl or

phenyloxycarbonyl group; the acetal-or ketal-type protecting group can be, for example, methylene, ethylene, isopropylidene or butylidene groups; and the ether-type protecting group can be, for example, an alkyl, alkenyl or benzyl group.

In another aspect, dehalogenation can be carried out in the presence of reductive dehalogenating agent. The reductive dehalogenating agent can be, for example, one or more of a metal catalyst in the presence of hydrogen, a metal hydride complex, an organic tin hydrides in the presence of radical initiator, an alkali metal aluminum hydride, or mixtures thereof. The metal catalyst can be, for example, palladium-carbon, palladium black, Raney-Nickel, platinum black, platinum dioxide or mixtures thereof ; the metal hydride complex can be, for example, sodium borohydride, potassium borohydride, lithium borohydride, sodium trimethoxy borohydride or mixtures thereof ; the organic tin hydride can be, for example, tributyltin hydride, diethyltin hydride, triphenyl tin hydride or mixtures thereof ; and the alkali metal aluminum hydride can be, for example, lithium aluminum hydride, sodium aluminum hydride or mixtures thereof. In yet another aspect, the dehalogenation comprises hydrogenation at a pressure of at least 4.0 kg/cm2 in the presence of a metal catalyst. The hydrogenation can also be carried out at a about 4.0 kg/cm2 to about 6.0 kg/cm2. This reaction can be carried out in one or more solvent that is inert under reaction conditions. Such solvents can be, for example, water, alcohol, ketone, ether, nitrile, chlorinated hydrocarbon, ester, dipolar aprotic solvent, cyclic ether or mixtures thereof.

Also provided herein are processes for the preparation of compounds of Formula II, Formula 11 comprising dehalogenating a compound of Formula III,

Formula III by hydrogenation at a pressure of at least 4.0 kg/cm2 in the presence of a metal catalyst, wherein R can be a hydrogen atom or hydroxyl protecting group and X can be halogen.

, Also provided herein are processes for the preparation of voglibose comprising the steps of reacting a compound of Formula I

Formula I with dihydroxyacetone and one or more reducing agent, followed by deprotection when R is a hydroxyl protection group, wherein R can be a hydrogen atom or hydroxyl protecting group and X can be halogen. The one or more reducing agent can be one or more of an alkali metal borohydride, an alkali metal aluminum hydride, an alkali metal cyanoborohydride, a metal catalyst in the presence of hydrogen, a dialkyl amine borane or mixtures thereof.

In one aspect, reaction of the compound of Formula I with dihydroxyacetone can be carried out in the presence of an acid to maintain a pH in the range of from about 6 to about 6.5. The compound of Formula I can be prepared by reacting the compound of Formula II Formula 11 with ammonium acetate or ammonium formate and one or more reducing agent, to form a compound of Formula I. The compound of Formula II can be formed by dehalogenating a compound of Formula III,

Formula III to form a compound of Formula II.

Also provided herein are processes for preparing voglibose comprising reacting the compound of Formula II

Formula 11 with 2-amino-1, 3-propanediol and one or more reducing agent, followed by deprotection when R is a hydroxyl deprotecting group, wherein R can be a hydrogen atom or a hydroxyl deprotecting group. The compound of Formula II can be formed by dehalogenating a compound of Formula III,

Formula III wherein R can be a hydrogen atom or hydroxyl protecting group and X can be halogen.

The one or more reducing agent can be one or more of an alkali metal borohydride, an alkali metal aluminum hydride, an alkali metal cyanoborohydride, a metal catalyst in the

presence of hydrogen, a dialkyl amine borane or mixtures thereof. The reaction of compound of Formula II with 2-amino-1, 3-propanediol can be carried out in the presence of an acid to maintain a pH in the range of from about 7 to about 7.5. In one aspect, the deprotection can be carried out by hydrogenation in the presence of metal catalyst and an acid to maintain a pH below 3.

Also provided are processes for preparing voglibose comprising deprotecting a compound of Formula I

Formula I when R is a hydroxyl protecting group to obtain valiolamine followed by reaction of valiolamine with dihydroxy acetone and one or more reducing agent, wherein R can be a hydrogen atom or a hydroxyl protecting group. The one or more reducing agent can be one or more of an alkali metal borohydride, an alkali metal aluminum hydride, an alkali metal cyanoborohydride, a metal catalyst in the presence of hydrogen, a dialkyl amine borane or mixtures thereof. The compound of Formula I can be prepared by reacting the compound of Formula II Formula II with ammonium acetate or ammonium formate and one or more reducing agent, to form a compound of Formula I. The compound of Formula II can be formed by dehalogenating a compound of Formula III, Formula III to form a compound of Formula II.

Also provided herein are compounds formed by a process comprising reacting a compound of Formula II,

Formula 11 with ammonium acetate, ammonium formate or a mixture thereof and one or more reducing agent, wherein R can be a hydrogen atom or a hydroxyl protecting group.

Also provided herein are compounds formed by a process comprising dehalogenating a compound of Formula III,

Formula III by hydrogenation at a pressure of at least 4.0 kg/cm2 in the presence of a metal catalyst, wherein R can be a hydrogen atom or a hydroxyl protecting group and X can be halogen.

Also provide herein are compounds formed by a process comprising the steps of : reacting a compound of Formula I

Formula I with dihydroxyacetone and one or more reducing agent, followed by deprotection when R is a hydroxyl protection group, wherein R can be a hydrogen atom or hydroxyl protecting group and X can be halogen.

Also provided herein are compounds formed by a process comprising reacting the compound of Formula II

Formula 11 with 2-amino-1, 3-propanediol and one or more reducing agent, followed by deprotection when R is a hydroxyl deprotecting group, wherein R is a hydrogen atom or a hydroxyl deprotecting group.

Also provided herein are compounds formed by a process comprising deprotecting a compound of Formula I

Formula I when R is a protecting group to obtain valiolamine followed by reaction of valiolamine with dihydroxy acetone and one or more reducing agent, wherein R can be a hydrogen atom or a hydroxyl protecting group.

Detailed Description of the Invention There is provided herein a process for the preparation of compounds of Formula I,

Formula I and pharmaceutical acceptable salts thereof, comprising reacting a compound of Formula II,

Formula 11 with ammonium acetate or ammonium formate and a reducing agent, wherein R can be a hydrogen atom or hydroxyl protecting group.

There also is provided herein a process for the preparation of compounds of Formula II, comprising dehalogenating a compound of Formula III

Formula III by hydrogenation at a pressure of at least 4.0 kg/cm2 in the presence of a metal catalyst, wherein R can be a hydroxyl protecting group and X can be a halogen. The halogen can be, for example, F, Cl, Br or I.

If required, the compounds provided herein can be further converted to its pharmaceutically acceptable salt, such as alkali, alkali earth or ammonium salt, by treating with suitable salt forming agent.

Examples of hydroxyl protecting groups include acyl-type protecting groups, acetal-or ketal-type protecting groups and ether-type protecting groups. Examples of acyl-type protecting groups include optionally substituted alkanoyl, benzoyl, alkoxycarbonyl, alkenyloxycarbonyl, benzyloxycarbonyl or phenyloxycarbonyl group.

Examples of ether-type protecting groups include alkyl, alkenyl or benzyl groups.

Examples of acetal-or ketal-type protecting groups include methylene, ethylene, isopropylidene or butylidene groups.

The compound of Formula II can also be obtained by the process above or a conventional process, for example, a process disclosed in U. S. Patent Nos. 4,824, 943 and 4,898, 986; and J. Org. Chem., 57: 3642 (1992), which are incorporated herein by reference. In particular, the compound of Formula II can be prepared by dehalogenation of the compound of Formula III.

Examples of reducing agents include alkali metal borohydride, alkali metal aluminum hydride, alkali metal cyanoborohydride, dialkyl amine boranes, metal catalyst in the presence of hydrogen or mixtures thereof. Examples of alkali metal borohydride include sodium borohydride, potassium borohydride, lithium borohydride, sodium trimethoxy borohydride or mixtures thereof. An example of an alkali metal cyanoborohydride includes sodium cyanoborohydride. Examples of metal catalysts include palladium-carbon, palladium black, Raney-nickel, platinum black, platinum dioxide, rhodium-carbon or mixtures thereof. Examples of alkali metal aluminum hydrides include lithium aluminum hydride, sodium aluminum hydride or mixtures thereof. An example of dialkyl amine borane includes dimethylamine borane.

In the reaction of compound of Formula II with ammonium acetate or ammonium formate to obtain the compound of Formula I, the reducing agent can be added simultaneously with ammonium acetate or ammonium formate, for example, when the reducing agent is sodium cyanoborohydride. The reducing agent can also be added after the reaction of compound of Formula II with ammonium acetate or ammonium formate, for example, when the reducing agent is a metal catalyst in the presence of hydrogen.

The reaction can be carried out in the presence of suitable solvents. Suitable solvents include, for example, organic solvents that are inert under reaction conditions.

Examples of such solvents include water; alcohols, for example, methanol, ethanol, isopropanol or butanol; ketones, for example, acetone or methyl isobutyl ketone; ethers, for example, diethylether, diisopropylether or dimethoxyethane; nitriles, for example, acetonitrile; chlorinated hydrocarbons, for example, methylene chloride, ethylenedichloride or carbon tetrachloride; esters, for example, ethylacetate or isopropylacetate; dipolar aprotic solvents, for example, dimethylsulfoxide or dimethylformamide ; cyclic ethers, for example, dioxane or tetrahydrofuran; or mixtures thereof.

The compound of Formula III can be prepared by processes disclosed in U. S.

Patent No. 4,898, 986 and J. Org. Chem., 57: 3642 (1992).

The dehalogenation reaction can be carried out in the presence of a reductive dehalogenating agent. Examples of dehalogenating agents include one or more metal catalysts in the presence of hydrogen, the metal catalysts being, for example, palladium- carbon, palladium black, Raney-nickel, platinum black or platinum dioxide; metal hydride complexes, for example, sodium borohydride, potassium borohydride, lithium borohydride or sodium trimethoxy borohydride; organic tin hydrides, for example, tributyltin hydride, dibutyltin hydride, diethyltin hydride or triphenyl tin hydride in the presence of radical initiator (e. g., azobisisobutyronitrile or benzoylperoxide); or alkali metal aluminum hydrides, for example, lithium aluminum hydride or sodium aluminum hydride.

The dehalogenation reaction can be carried out in the presence of suitable solvents.

Suitable solvents include, for example, organic solvents that are inert under reaction conditions. Examples of such solvents include water; alcohols, for example, methanol, ethanol, isopropanol or butanol; ketones, for example, acetone or methyl isobutyl ketone; ethers, for example, diethylether, diisopropylether or dimethoxyethane; nitriles, for example, acetonitrile; chlorinated hydrocarbons, for example, methylene chloride, ethylenedichloride or carbon tetrachloride; esters, for example, ethylacetate or isopropylacetate; dipolar aprotic solvents, for example, dimethylsulfoxide or dimethylformamide ; cyclic ethers, for example, dioxane or tetrahydrofuran; or mixtures thereof.

The temperatures at which the reactions of the processes provided herein may be carried out are not critical. For example, such reactions can be performed at temperatures from about 20 °C to about 120 °C. In other embodiments, the reactions can be performed at temperatures from about 25 °C to 50 °C.

Pressure significantly affects the dehalogenation reaction carried out in the presence of metal catalyst in the presence of hydrogen. Catalytic hydrogenation at pressures less than 4.0 kg/cm2 lead to the formation of the corresponding mono halogenated product and/or mixture of deprotected products. For example, catalytic hydrogenation carried out at pressures of about 2.5 or 3.5 kg/cm2 typically gives an HPLC output purity of between about 60-75 % for (1 S)-(l (OH), 2, 4/1, 3) -2,3, 4-tri-O-benzyl-5- oxo-l-C- [benzyloxymethyl]-1, 2,3, 4-cyclohexanetetrol; 15-19 % for debenzylated side products and between about 1-7 % monochloro product. In contrast, catalytic hydrogenation carried out at a pressure of 4.50 kg/cm2 typically gives an HPLC output purity of between about 94 % for (lS)- (l (OH), 2, 4/1, 3) -2,3, 4-tri-O-benzyl-5-oxo-1-C- [benzyloxymethyl]-1, 2,3, 4-cyclohexanetetrol; less than 1 % for debenzylated side products and less than about 2 % monochloro product.

The mixture of deprotected compounds formed as a side product carries forward in the next step where the compound of Formula II is reacted with ammonium acetate to form compound of Formula I and tends to form a dimmer impurity which affects the isolation of the product, yield and purity of the final product. The reaction may be carried out at about 4.0 to about 6.0 kg/cm2 in some particular embodiments.

Further, the compound of Formula II may be converted to voglibose by reacting the compound of Formula II with 2-amino-1, 3-propanediol in the presence of a reducing agent followed by deprotection in the event that R is a protecting group. The reaction with 2-amino-1, 3-propanediol can be carried out in the presence of an acid. In other embodiments, the pH can be maintained in the range of from about 7.5 to about 8 in some particular embodiments.

Alternatively, compound of Formula II may be converted to compound of Formula I, for example, by methods disclosed in U. S. Patent No. 4,898, 986; and J. Org. Chem., 57: 3642 (1992) which are incorporated herein by reference. U. S. Patent No. 4,898, 986 and J. Org. Chem., 57: 3642 (1992) disclose the conversion of the n-oxime of valiolone to

valiolamine by reaction using Raney-nickel. U. S. Patent No. 4,824, 943 discloses the conversion of valeinamine to valiolamine using a multistep synthetic route.

Further, the compound of Formula I can be converted to voglibose by a process comprising the steps of reacting the compound of Formula I with dihydroxy acetone and a reducing agent, followed by deprotection in the event that R is a hydroxyl-protecting group. This reaction can be carried out in the presence of an acid, and in particular to maintain a pH in the range of from about 6 to about 6.5.

Alternatively, the compound of Formula I can be converted to voglibose by a process comprising deprotecting the compound of Formula I (in the event that R is a protecting group) to obtain valiolamine, followed by reaction of valiolamine with dihydroxy acetone and a reducing agent.

The above processes of converting a compound of Formula I to voglibose, can be carried out in the same solvents as those listed above for reacting a compound of Formula II with ammonium acetate or ammonium formate.

The product obtained by the reaction of a protected compound of Formula I with dihydroxyacetone and by the reaction of a compound of Formula II with 2-amino-1, 3- propanediol, wherein R is hydroxyl protecting group, can be deprotected by conventional means or methods known in the art, include those described in U. S. Patent Nos. 4,824, 943, 4,898, 986; and J. Org. Chem., 57: 3642 (1992), which are incorporated herein by reference. The acetal-or ketal-type protecting groups can be removed by acid hydrolysis.

The acyl-type protecting group can be removed by alkali hydrolysis. When R is benzyl, hydrogenation in the presence of metal catalyst is utilized to obtain voglibose. The hydrogenation can be carried out in the presence of an acid to maintain a pH below 3 in some particular embodiments.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

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 these examples would be evident to

persons ordinarily skilled in the art.

EXAMPLES Example 1: Synthesis of (1S)-(1(OH), 2,4/1, 3) -2,3, 4-tri-O-benzyl-5-oxo-1-C- [benzyloxymethyll-1, 2,3, 4-cyclohexanetetrol To a solution of (lS)-(l (OH), 2, 4/1, 3) -2,3, 4-tri-O-benzyl-6, 6-dichloro-5-oxo-1-C- [benzyloxymethyl]-1, 2,3, 4-cyclohexanetetrol (7.0 kg, HPLC purity: 92. 11%) in tetrahydrofuran (28 L) and methanol (70 L) was added sodium acetate (4.66 kg) and 10% Pd/C (4.2 kg) at room temperature. The suspension was stirred for 8-10 hours at 23-25 °C at a hydrogen pressure of 4.5 0.2 kg/cm2. The reaction mixture was filtered through HYFLOTM (celite) and the celite bed was washed with methanol and tetrahydrofuran mixture (1: 1,5 L). The combined filtrate was concentrated under reduced pressure at 40- 45 °C. Water (25 L) was then added to the concentrated residue and was extracted with ethyl acetate twice (20 L each). The ethyl acetate layer was concentrated under reduced pressure. Diisopropyl ether (7 L) was then added and the mixture was cooled to 10-15 °C, and stirred for 30 minutes. The product was filtered at 10 °C, washed with diisopropyl ether (2 L) and dried under reduced pressure at 30-35 °C.

Yield: 4. 55 kg HPLC purity: 94.09% 'HNMR (CDCl3), 8 : 2.39 (brs, 1H), 2.47 (1H, d, J=14.4Hz), 2.84 (1H, d, J = 14.7Hz), 3.15, 3.53 (1H each, ABq, J=8.4Hz), 4.01-4. 14 (3H, m), 4.42-4. 57 (4H, m), 4.74 (1H, d, J=10.8Hz), 4.93-5. 0 (3H, m), 7.16-7. 38 (20H, m) The experiments were repeated at hydrogen pressures of 2.5 kg/cm2 and 3.5 kg/cm2 with all other conditions being identical and results are tabulated in Table 1.

Example 2: Synthesis ofBSMKOH). 2. 4/1. 3)-2, 3. 4-tri-0-benzyl-5-oxo-l-C- rbenzvloxvmethyll-1, 2, 3. 4-cyclohexanetetrol To a solution of (lS)-(l (OH), 2, 4/1, 3) -2,3, 4-tri-O-benzyl-6, 6-dichloro-5-oxo-1-C- [benzyloxymethyl]-1, 2,3, 4-cyclohexanetetrol (7.0 kg, HPLC purity: 92. 11%) in tetrahydrofuran (28 L) and methanol (70 L) was added sodium acetate (4.66 kg) and 10%

Pd/C (4.2 kg) at room temperature. The suspension was stirred for 8-10 hours at 23-25 °C at a hydrogen pressure of 4.5 0.2 kg/cm2. The reaction mixture was filtered through HYFLOTM (celite) and the celite bed was washed with methanol and tetrahydrofuran mixture (1: 1, 5 L). The combined filtrate was concentrated under reduced pressure at 40- 45 °C. Water (25 L) was then added to the concentrated residue and extracted with ethyl acetate twice (20 L each). The ethyl acetate layer was concentrated under reduced pressure. Methanol (36 L) was then added to the residue, about 20 L of methanol was distilled off from the reaction mixture under vacuum at 40 °C to 45 °C, leaving behind 16 L of a methanolic mixture. The mixture was heated to dissolve solid, cooled to 20 °C, and stirred at this temperature for 1 hour. The product was filtered at 20 °C, washed with methanol (2 L) and dried under reduced pressure at 30-35 °C.

Yield: 4. 2 kg HPLC purity: 97 % Example 3: Synthesis of (1SL (1 (OH), 2, 4/1, 3)-2, 3, 4-tri-O-benzyl-5-oxo-1-C- [benzvloxymethyll-1, 2, 3, 4-cyclohexanetetrol To a solution of (lS)-(l (OH), 2, 4/1, 3) -2,3, 4-tri-O-benzyl-6, 6-dichloro-5-oxo-l-C- [benzyloxymethyl]-1, 2,3, 4-cyclohexanetetrol (15 g, 24.15 mmol) in methanol and tetrahydrofuran (2.5 : 1,190 mL) were added 10% palladium carbon (7 g), sodium acetate (7.0 g, 85.33 mmol) and water (4 mL), and the mixture was hydrogenated with shaking for 6 hours at 3.5 to 4.0 kg/cm2 pressure at room temperature. The solid was removed by filtration and washed with methanol. Combined filtrate and washings were concentrated and the residue was partitioned between ethylacetate and water. The ethylacetate layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was crystallized in diisopropyl ether to obtain white crystalline product.

Yield: 9.2 g HPLC purity: 90. 19 % 'HNMR (CDC13), 8 : 2. 39 (brs, 1H), 2.47 (1H, d, J=14. 4Hz), 2.84 (1H, d, J = 14. 7Hz), 3.15, 3.53 (1H each, ABq, J=8.4Hz), 4.01-4. 14 (3H, m), 4.42-4. 57 (4H, m), 4.74 (1H, d, J=10.8Hz), 4.93-5. 0 (3H, m), 7.16-7. 38 (20H, m)

Example 4: Synthesis of (lS)- (l (OH), 2, 4, 5/1, 3)-2, 3, 4-tri-O-benzvl-5-amino-1-C- [benzyloxvmethvl-1, 2, 3, 4-cyclohexanetetrol To a solution of (lS)-(l (OH), 2, 4/1, 3) -2,3, 4-tri-O-benzyl-5-oxo-1-C- [benzyloxymethyl]-1, 2,3, 4-cyclohexanetetrol (4.0 g, 7.25 mmol) in methanol (20 mL) were added ammonium acetate (6.0 g, 77.92 mmol) and sodium cyanoborohydride (1.0 g, 15.91 mmol). The mixture was stirred for 7 hours at ambient temperature. Water (20 mL) was added to the mixture and extracted twice with ethylacetate (20mL each). The organic layer was washed with water and brine solution and concentrated to give the title compound as a colorless syrup.

Yield: 4.0 g HPLC purity: 90 % 'HNMR (CDCl3 + D2O, 300MHz), o : 1.76 (1H, dd, J=2. 6,14. 6Hz), 1.80 (1H, dd, J=2.5, 14.6Hz), 3.20-3. 60 (5H, m), 4.18 (1H, t, J=9.6Hz), 4.40 (2H, s), 4.60-4. 91 (6H, m), 7.25 - 7. 36 (20H, m) Example 5: Synthesis of (1S)- (1 (OH), 2, 4, 5/1, 3)-2, 3, 4-tri-O-benzvl-5-amino-1-C- [benzYloxymethvl]-1, 2, 3, 4-cyclohexanetetrol To a solution of pure (l S)-(l (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 for 7 to 8 hours at 30-35 °C. The solvent was distilled off under reduced pressure and water (250 mL) was then added 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 a 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 was separated. Diisopropylether (100 mL) was added to the thick lower product layer, and stirred at 45-50 °C for 30 minutes. The resulting thick lower product layer was separated, and concentrated to dryness to give the title compound as a colorless foamy solid.

Yield: 49 g

HPLC Purity: 88.1% Example 6: Synthesis of (1S)- (1 (OH), 2, 4, 5/1, 3)-Samino-1-C-hvdroxymethyl-1, 2, 3, 4- cyclohexanetetrol To a solution of (lS)- (l (OH), 2,4, 5/1, 3) -2,3, 4-tri-O-benzyl-5-amino-1-C- [benzyloxymethyl]-1, 2,3, 4-cyclohexanetetrol (2.26 g, 4.1 mmol) in mixtures of methanol and tetrahydrofuran (1: 1,50 mL) were added 10% palladium carbon (1.4 g) and 4% hydrochloric acid solution (16.5 mL). The mixture was hydrogenated with shaking for 4.5 hours at 2.5-3. 0 kg/cm2 at 40 °C. The reaction mixture was filtered and washed with methanol. The combined filtrate was concentrated and the resulted residue was chromatographed using ion exchange resin (Indion 225 H+) to give the title compound.

Yield: 0.65 g HPLC Purity: 98.76 % 1H NMR (D2O, 6) : 1.94 (lH, dd, 6Hax. ), 2.11 (lH, dd, 6Heq. ), 3.48 (lH, q, 5H), 3.53 (lH, d, 2H), 3.56&3. 59 (each IH,-CH20-), 3.61 (lH, dd, 4H), 3.86 (lH, t, 3H) Example 7: Synthesis of (1S)-(1(OH),2,4,5/1,3)-2,3,4-tri-O-benzyl-5-[[2-hydroxy-1- (hydroxymethyl) ethyll amino]-1-C-rbenzvloxvmethyl]-1, 2,3, 4-cyclohexanetetrol 1,3-dihydroxyacetone (50. 0g, 0.278 mol) was added to a solution of (1S)- (1 (OH), 2,4, 5/1, 3) -2,3, 4-tri-O-benzyl-5-amino-1-C-[benzyloxymethyl]-1, 2,3, 4- cyclohexanetetrol (50.0 g, 0.09 mol) in methanol (500 mL) at 25-30 °C and stirred for 60 minutes. Sodium cyanoborohydride (18 g, 0.287 mol) and concentrated hydrochloric acid were then added to the reaction mixture to adjust the pH to about 6.0 and stirred for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The ethylacetate layer was dried over anhydrous sodium sulfate and concentrated to obtain the title compound as a pale yellow-colored syrup.

Yield: 57.0 g 'HNMR (CDC13), 5 : 1.60 (1H, dd, J=2.1, 15Hz), 1.92 (1H, dd, J=2. 7, 15Hz), 2.75 (lH, m), 3.20 (1H, d, J=8.4Hz), 3.44 (1H, m), 3. 50-3. 69 (7H, m), 4.10 (lH, m), 4. 39 (2H, s), 4. 56 - 4. 94 (6H, m), 7.22-7. 36 (20H, m)

Example 8: Synthesis of (IS)- (I (OH), 2, 4, 5/1, 3)-2, 3, 4-tri-O-benzyl-5-- [ [2-hydroxy-l- (hydroxymethyl)ethyl]amino]-1-C-[benzyloxymethyl]-1,2,3,4-cy clohexanetetrol 1,3-dihydroxyacetone (2.6g, 28.86 mmol) was added to a solution of (1S)- (1 (OH), 2,4, 5/1, 3) -2,3, 4-tri-O-benzyl-5-amino-1-C-[benzyloxymethyl]-1, 2,3, 4- cyclohexanetetrol (4.0 g, 7.23 mmol) in methanol (40 mL) at ambient temperature and stirred for 30 minutes. Sodium cyanoborohydride (1.8 g, 28.64 mmol) and catalytic amount of concentrated hydrochloric acid were then added to the reaction mixture and stirred overnight. The reaction mixture was partitioned between water and ethyl acetate.

The ethylacetate layer was dried over anhydrous sodium sulfate and concentrated to obtain title compound as a pale yellow-colored syrup.

Yield: 4.2 g HPLC Purity: 70 % 'HNMR (CDCl3), # : 1.60 (1H, dd, J=2.1, 15Hz), 1.92 (1H, dd, J=2.7, 15Hz), 2.75 (lH, m), 3.20 (1H, d, J=8.4Hz), 3.44 (1H, m), 3. 50-3. 69 (7H, m), 4.10 (lH, m), 4. 39 (2H, s), 4. 56 - 4. 94 (6H, m), 7.22-7. 36 (20H, m) Example 9: Synthesis of (1S)-(1(OH),2, 4, 5/1, 3)-2,3,4-tri-O-benzyl-5--[[2-hydroxy-1- (hydroxYmethYl) ethJamino]-1-C-rbenzyloxymethvl]-1, 2, 3, 4-cyclohexanetetrol 2-amino-1, 3-propanediol (20. 1g, 220 mmol) was added to a solution of (lys)- (l (OH), 2, 4/1, 3) -2,3, 4-tri-O-benzyl-5-oxo-1-C-[benzyloxymethyl]-1, 2,3, 4- cyclohexanetetrol (35.0 g, 63.4 mmol) in methanol (350 mL) at ambient temperature and stirred for 60 minutes. Sodium cyanoborohydride (14 g, 222 mmol) was then added to the reaction mixture. Concentrated hydrochloric acid was added to adjust pH to about 8.0 and the reaction mixture was stirred overnight. The reaction mixture was partitioned between water and ethyl acetate. Ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to obtain title compound as pale yellow-colored syrup.

Yield: 38.6 g HPLC Purity: 90.0%

IHNMR (CDC13), 8 : 1.60 (1H, dd, J=2.1, 15Hz), 1.92 (1H, dd, J=2.7, 15Hz), 2.75 (lH, m), 3.20 (1H, d, J=8.4Hz), 3.44 (1H, m), 3. 50-3. 69 (7H, m), 4.10 (IH. m), 4. 39 (2H, s), 4. 56 - 4. 94 (6H, m), 7.22-7. 36 (20H, m) Example 10 : Synthesis of (IS)- (OH), (OH),2,4,5/1,3)-5-[[2-hydroxy-1-(hydroxymethyl) ethyls amino]-1-C- (hvdroxymethyl)-1, 2, 3, 4-cyclohexanetetrol (Voglibose) To a solution of (lS)-(l (OH), 2,4, 5/1, 3) -2,3, 4-tri-O-benzyl-5-- [ [2-hydroxy-1- (hydroxymethyl) ethyl] amino]-1-C- [benzyloxymethyl]-1, 2,3, 4-cyclohexanetetrol (13.0 g, 20.73 mmol) in methanol : tetrahydrofuran (1: 1,260 mL) were added 10 % palladium- carbon (13 g) and 4% hydrochloric acid solution (20 mL), and the mixture was hydrogenated with shaking for 3 hours at 3.0-3. 5 kg/cm2 at room temperature. The solid was removed by filtration and washed with methanol. The combined filtrate and washings were concentrated. The resulted residue was chromatographed on a column equipped with INDION 890 resin [Ion exchange (India) Ltd. ] with water. The eluent was evaporated under reduced pressure and then treated with ethanol to remove traces of water. Methanol (50 mL) was then added to the residue and stirred at room temperature for 1 hour. The mixture was then filtered and voglibose was obtained as white solid.

Yield: 1.5 g HPLC Purity: 97% 'HNMR (D20, 6) : 1. 55 (lH, dd, J: 2.1, 15Hz), 2.10 (lH, dd, J: 2.7, 15Hz), 2.90 (lH, m), 3.40- 3.55 (2H, m), 3.59 (2H, m), 3.64-3. 80 (5H, m), 3.88 (lH, t, J: 9.6Hz).