FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PREPARATION OF INTERMEDIATE 1-C-ALKYL HEXOPYRANOSE"
2. APPLICANT:
(a) NAME: 1NDOCO REMEDIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Indoco House, 166 C.S.T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention relate to one pot process for the preparation of intermediate 1-C-alkyl hexopyranose compound of Formula I useful in the preparation of Valienamine, Valiolamine and their N-substituted derivative.

Formula 1 Wherein R is halo group selected from chlorine, bromine & iodine; and R1 is hydroxyl protecting group.
BACKGROUND AND PRIOR ART:
Valienamine, valiolamine and their N-substituted derivatives have an inhibitory activity against a-glucosidase and are useful as prophylactic or therapeutic agents of hyperglycemic symptoms in man and other animals and various disorders caused by hyperglycemia such as diabetes, obesity, hyperlipemia etc.
The compound 1-C-alkyl hexopyranose of Formula I have been prepared in two step process, wherein the compound glucopyranose on oxidation reaction yields corresponding gluconolactone which on further reaction with lithium diisopropylamide in suitable solvents results in the compound 1-C-alkyl hexopyranose. The following methods for oxidation of glucopyranose were reported in the literature, using acetic anhydride with dimethyl sulfoxide (Tetrahedron; vol. 50, 14, (1994); p. 4215-4224), with tetrapropylammonium perruthennate, 4-methylmorpholine N-oxide and molecular sieve in suitable solvent (Bioorganic and Medicinal Chemistry; vol. 18, 6, (2010); p. 2178-2194). with Jones reagent in acetone (Chemistry-An European Journal; vol. 8, 8, (2002); p. 1872-1878), with bromobenzene, potassium carbonate, triphenylphosphine and palladium diacetate in tetrahydrofuran (Carbohydrate Research; vol. 339, 7, (2004); p. 1377-1380) and oxidation using molar equivalent of 4-acetylamino-2,2,6,6-

tetramethylpiperidine-1-oxoammonium tetrafluoroborate in pyridine and suitable solvent (Tetrahedron Letters, 42 (2001), 8793-8796). The compound gluconolactone obtained are potentially unstable compounds and needs to be utilized for the next step as early as possible protecting from the moisture.
In the second step the isolated gluconolactone undergoes deprotonation in presence of strong base resulting in the formation of the compound 1-C-alkyl hexopyranose of Formula I.
The drawbacks in the above prior arts are,
i. use of highly acidic medium (Jones reagent) of the reaction;
ii. use of controlled substance like acetic anhydride which makes it difficult to use
on industrial scale; iii. use of triphenylphosphine generates unwanted sludge of triphenylphosphine oxide which is difficult to remove from the reaction mass and creates problem of disposal on industrial scale: iv. isolation and use of unstable gluconolactone compound.
It is evident from the prior art that there remains a need for an improved process to prepare the compound 1-C-alkyl hexopyranose of Formula I which avoids multiple process steps and uses environment friendly reagents.
The present inventors have conducted diligent investigation for solving the aforementioned problems and have succeeded in preparing the compound 1-C-alkyl hexopyranose of Formula I, with an improved one pot process which carries out the oxidation reaction of glucopyranose compound in presence of catalyst and the compound gluconolactone formed is reacted insitu in presence of base to isolate the compound 1-C-alkyl hexopyranose of Formula I.
SUMMARY OF THE INVENTION:
The present invention provides a one pot process for the preparation of the compound 1-C-alkyl hexopyranose of Formula I;

Formula I [where R is halo group selected from chlorine, bromine & iodine; and R| is a hydroxyl protecting group], comprising the steps of reacting glucopyranose compound of Formula II

Formula II where R1 is a hydroxyl protecting group. with sodium hypochlorite in presence of a buffer and a catalyst to form an intermediate gluconolactone compound, which on insitu reaction with base in presence of solvent results in the compound of Formula I.
DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention describes the process in detail for the preparation of the compound 1-C-alkyl hexopyranose of Formula I

Formula I [wherein R is halo group selected from chlorine, bromine or iodine; and R1 is hydroxyl protecting group]; involving oxidation reaction of glucopyranose compound of Formula
II;

Formula II [wherein R1 is a hydroxyl protecting group], with sodium hypochlorite in presence of buffer and catalyst to form the intermediate compound, which on in situ reaction with base in presence of solvent results in the formation of the required compound of Formula I.
In the above Formula I and Formula II, the hydroxyl protective groups represented by R1. are selected from protective groups established in the chemistry of sugars, such as ether type protecting groups. The preferred hydroxyl protecting groups are benzyl, p-methoxybenzyl, t-butyl. methoxymethyl, tetrahydropyranyl. The most preferred hydroxy] protecting group used for this invention is benzyl.
The compound hydroxyl protected glucopyranose used for this invention is easily available or can be synthesized from cheaply available D-glucose.
In one embodiment of the present invention, the oxidation reaction of glucopyranose compound of Formula II was carried out using sodium hypochlorite in presence of buffer and catalyst using dichloromethane as solvent.
The buffer used for the reaction is selected from mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate, sodium dihydrogen phosphate and disodium hydrogen phthalate, disodium hydrogen phthalate and potassium dihydrogen phosphate, sodium carbonate and acetic acid, sodium bicarbonate and acetic acid, and potassium dihydrogen phosphate and sodium hydroxide. The preferred buffer used for the oxidation reaction is

mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate or a mixture of sodium bicarbonate and acetic acid, wherein the most preferred buffer used for the oxidation reaction is mixture of sodium bicarbonate and acetic acid.
The buffer and sodium hypochlorite solution used for the oxidation reaction in the present invention are either charged separately or mixed together and charged to the reaction mass depending on the mixture of compound used as buffer.
The catalyst used for the oxidation reaction is 2,2,6,6-tetramethylpiperidine-l-oxyl. The oxidation reaction is carried out at temperature in the range of -5°C to 35°C the preferred temperature for oxidation reaction is 0°C to 10°C. The reaction is carried out in presence of saturated solution of sodium bicarbonate prepared in water. The intermediate compound gluconolactone obtained after oxidation is taken insitu, for the next step without isolation.
Accordingly the compound 2,3.4.6-tetra-0-benzyl-D-glucopyranose is dissolved in solvent dichloromethane and cooled the solution to 0°C. Prepared the buffer solution by mixing sodium dihydrogen phosphate and disodium hydrogen phosphate in water and charged the catalyst 2,2.6.6-tetramethylpiperidine-l-oxyl and the buffer solution to the reaction mixture maintaining temperature at 0°C to 5°C. Charged to the reaction mixture saturated solution of sodium bicarbonate in water under stirring. Slowly charged sodium hypochlorite solution maintaining the temperature between 0°C to 5°C. The pH of the reaction mixture is maintained at 6 to 7 by adding aqueous solution of sodium dihydrogen phosphate. The completion of the reaction is monitored on TLC. The reaction after completion is quenched by adding sodium thiosulphate and stirred. Slowly raised the temperature of the reaction mixture to 20°C to 30°C and separated the organic layer. Extracted the aqueous layer further with additional dichloromethane and checked for the absence of the product in the aqueous layer. Combined organic layer is washed with water and dried over anhydrous sodium sulphate. Concentrated the organic layer to one third of the volume and cooled the residual solution containing the intermediate gluconolactone to 25°C and subsequently to -65°C.

Charged slowly cooled solution of lithium diisopropylamide in tetrahydrofuran to the cooled residual solution maintaining temperature at -70°C to -65°C under continuous nitrogen atmosphere. Maintained the reaction at -70°C to -65°C and monitored the completion of the reaction on TLC. After completion of the reaction, raised the temperature slowly to -30°C and diluted the reaction mixture with solvent dichtoromethane. Quenched the reaction mass with aqueous 2N hydrochloric acid solution and raised the temperature of the reaction mass to 25°C to 30°C. Stirred the reaction mass for 30 minutes, separated the organic layer and washed with saturated sodium bicarbonate solution. The organic layer is dried over anhydrous sodium sulphate and concentrated under reduced pressure below 40°C to get the crude residual oil of 2,3,4,6-tetra-O-benzyl-1 -C-(dichloromethyl)-D-glucopyranose.
In another embodiment of the present invention the crude product is taken for purification in a solvent selected from the group consisting of n-hexane, cyclohexane, diethyl ether. diisopropyl ether petroleum ether, methanol, isopropanol, n-propanol and butanol either alone or in combination thereof to get pure compound 2,3,4,6-tetra-O-benzyl-l-C-(dichloromethyl)-D-glucopyranose.
The compound 2,3,4,6-tetra-0-benzyl-l-C-(dichloromethyl)-D-glucopyranose (Formula I) is useful in the preparation of Valienamine. Valiolamine and their N-substituted derivatives which have an inhibitory activity against a-glucosidase.
The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.
Example:
Example 1: Preparation of 2,3,4,6-tetra-0-benzyl-l-C-(dichloromethyl)-D-glucopyranose:
Charged 2,3,4,6-tetra-O-benzyl-D-glucopyranose (25 g, 0.04624 mol) in dichloromethane (125 ml, 5vol) and stirred. The reaction solution was cooled to 0°C. Charged catalyst 2,2,6,6-tetramethylpiperidine-l-oxyl (0.2167g, 0.00138 mol, 0.03 eq), followed by

addition of buffer solution of pH 6 (prepared by mixing sodium dihydrogen phosphate (4.833g) and disodium hydrogen phosphate (5g in 100 ml water) and stirred. Charged saturated sodium bicarbonate (50 ml, 2voI) solution to the reaction mixture followed by slow addition of sodium hypochlorite solution (6.9 g, 0.009 mol, 450 ml, 2 eq) maintaining the temperature of the reaction mixture at 0°C to 5°C and pH at 6-7 by addition of 40 % solution of sodium dihydrogen phosphate. The progress of the reaction was monitored on TLC. After completion of the reaction, the reaction mixture was quenched by adding aqueous sodium thiosulphate (11.25 g in 50 ml 2 vol.) solution. Stirred the quenched reaction mixture for 10 to 15 minutes and slowly raised the temperature of the reaction mixture to 25°C. The organic layer was separated and extracted the aqueous layer with dichloromethane (2 x 75 ml). The combined organic layers were washed with water (3 x 150 ml) .The organic layer (275 ml) was dried over sodium sulphate and concentrated under reduced pressure till one third of the volume and cooled the residual solution containing the intermediate gluconolactone to 25°C and subsequently to -70°C.
Lithium diispropylamide preparation: To a solution of diisopropyi amine (11.08 g, 0.1095 mol, 2.37 eq) in THF (135 ml. 5.28 vol) a solution of n-Butyl lithium (1.6 molar solution. 46.5 ml, 0.11 mof, 2.37 eq) in n-hexane was added drop wise in a stream of nitrogen atmosphere at -20°C to -10°C. The solution was stirred at this temperature for 1 hour.
To the cooled residual solution, charged cooled solution of lithium diisopropylamide maintaining the temperature at -70°C to -65°C under blanket of nitrogen atmosphere and maintained under stirring till the completion of the reaction. The progress of the reaction was monitored by TLC. After the completion of the reaction, the temperature of the reaction mixture was raised to -30°C and charged dichloromethane (115 ml). Slowly charged aqueous solution of 2N hydrochloric acid (110 ml) and raised the temperature slowly to 25°C. Stirred the reaction mixture and maintained the temperature at 25°C to 30°C for 30 minutes. Separated the organic layer and washed with saturated bicarbonate solution (100 ml) followed by washing with saturated brine solution (100 ml). The separated organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get an oily crude residual mass of the compound 2,3,4,6-tetra-0-benzyl-l-C-(dichloromethyl)-D-glucopyranose. Charged diisopropyi ether (150 ml)

and stirred the solution at 0°C to 5°C for 6 to 8 hours to isolate solid mass of pure compound of 2,3,4,6-tetra-O-benzyl-! -C-(dichloromethyl)-D-g!ucopyranose. Weight= 19.8g
Example 2:
Charged 2,3,4,6-tetra-O-benzyl-D-glucopyranose (100 g) in dichloromethane(600 ml) and water (500ml) , stirred and cooled the mixture to 0 to 5°C. Charged catalyst 2,2,6,6-tetramethylpiperidine-1-oxyl (0.5 g) followed by addition of freshly prepared mixture of sodium hypochlorite solution, sodium bicarbonate and acetic acid (2200 ml) maintaining the temperature at 0 to 5°C. Progress of reaction was monitored on TLC. After completion of reaction, the reaction mixture was quenched by adding aqueous sodium thiosulphate (45 gm in 100 ml water) and stirred for 10-15 minutes and slowly raised the temperature to 25°C. The organic layer separated and extracted the aqueous layer with dichloromethane (1 x 100 ml). The combined organic layer was washed with water (3 x 500ml), dried over sodium sulphate and concentrated under reduced pressure till one third of the volume and cooled the residual solution containing the intermediate gluconolactone to 25°C and subsequently to -70°C.
Lithium diisopropylamide preparation: To a solution of diisopropyl amine (45.06 gm) in THF (192 ml), a solution of n-butyl lithium in n-hexane (1.6 M, 278,43ml) was added drop wise in stream of nitrogen atmosphere at -20°C to -10°C. The solution was stirred at this temperature for I hour.
To the cooled residual solution, charged cooled solution of lithium diisopropylamide maintaining the temperature at -75°C to -70°C under blanket of nitrogen atmosphere and maintained under stirring for 3 hours. After the completion of reaction, the temperature of the reaction mixture was raised to -30°C and charged dichloromethane (384ml), the temperature of the reaction mixture was raised to -5° to 0°C. Slowly added IN HC1 solution (950 ml) and raised the temperature slowly to 25°C. Stirred the reaction mixture at 25°C for 30 min. Separated organic layer washed with saturated sodium bicarbonate (1 x 950 ml) and saturated brine solution (950 ml). The separated organic layer was concentrated under reduced pressure to get crude residual mass of the compound 2,3,4,6-

tetra-0-benzyl-l-C-(dichloromethyl)-D-glucopyranose. Dissolved crude residual mass in isopropanol and passed through silica bed. washed silica bed with isopropanol (570 ml). Concentrated isopropanol solution under reduced pressure to half a volume and slowly cooled to 25°C to 30°C. Further cooled to 0°C to -5°C and stirred for two hours. Filtered at same temperature and washed cake with chilled isopropanol (95 ml) and dried the pure compound of 2,3,4,6-tetra-O-benzy 1-1-C-(dichloromethyI)-D-glucopyranose till constant weight. Weight = 80.75 g

We Claim:
1. A procees for the preparation of the compound 1-C-aIkyl hexopyranose of Formula I;

Formula \ wherein R is halo group selected from chlorine, bromine & iodine; and R1 is a hydroxy! protecting group, comprising the steps of; i, reacting glucopyranose compound of Formula II
Formula II
with sodium hypochlorite in presence of a buffer and a catalyst to form an
intermediate gluconolactone compound; ii. reacting in situ the gluconolactone compound with base in presence of solvent
to isolate compound of Formula 1; iii. purifying the compound of Formula I to obtain pure compound I.
2. The process according to claim 1, wherein the buffer used for the reaction in step (i) is selected from the group of mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate, sodium dihydrogen phosphate and disodium hydrogen phthalate, disodium hydrogen phthalate and potassium dihydrogen phosphate, sodium carbonate and acetic acid, sodium bicarbonate and acetic acid and potassium dihydrogen phosphate and sodium hydroxide.

3. The process according to claim 2, wherein the buffer used for the reaction is mixture of sodium bicarbonate and acetic acid.
4. The process according to claim 2, wherein the buffer used for the reaction is mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate.
5. The process according to claim 1; wherein the catalyst used in step (i) is 2.2,6,6-tetramethylpiperidine-l-oxyl.
6. The process according to claim 1, wherein the reaction with sodium hypochlorite is carried out at temperature range of-5°C to 35°C
7. The process according to claim 6, wherein the reaction with sodium hypochlorite is carried out at temperature of 0°C to 10°C.
8. The process according to claim I; wherein the base used in step (ii) is Lithium diisopropylamide.
9. The process according to claim 1; wherein the solvent used in step (ii) is selected from tetrahydrofuran and n-hexane and mixture thereof.
10. The process according to claim 1; wherein the solvent used for purifying in step (iii) is selected from the group of n-hexane, cyclohexane, diethyl ether, diisopropyl ether petroleum ether, methanol, isopropanol, n-propanol and butanol either alone or in combination thereof.
11. The process according to claim 10, wherein the solvent used for purifying is selected from di isopropyl ether and isopropanol.
12. The process according to claim I; wherein the reaction of glucopyranose with sodium hypochlorite is carried out at pH range of 6 to 7.