DESC:FIELD OF THE INVENTION
The present invention relates to improved process for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I).

(I)
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) is useful as intermediate in the preparation of anti-retroviral drugs.

BACKGROUND OF THE INVENTION
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I), is useful as intermediate in the preparation of anti-retroviral drugs such as Darunavir, Amprenavir etc. Anti-retroviral drugs are used to treat HIV infection.


(I)
WO 01/25240, EP 539192, Tetrahedron Letters, 1995, Vol.36, p.505 are discloses a process for synthesizing a racemic (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) using tributyltin hydride and ozone oxidation. These reagents are more hazardous and using for plant scale not suitable.
WO03024974A2 discloses the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) is based on photochemical cycloaddition reaction to give an oxetane intermediate which subjected to reduction, deprotection and rearrangement reaction. This process results in very low yield and requires expensive equipment for photochemical. This process also involves resolution in the final part of the synthesis.
US 2005/0256322 A1 discloses the key intermediate, an O-protected hydroxyacetyl-?-butyrolactone, is asymmetrically hydrogenated and subsequently reduced, deprotected and cyclized to give the undesired compounds. This process involves more number of steps and highly cost-inefficient.
The present invention is an improved, commercially viable and industrially advantageous process to achieve with improved yield and purity of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) using novel intermediates.

SUMMARY OF INVENTION
Particular aspects of the present invention relates to a process for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I). (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) obtained by the process of the present invention was found to substantially pure and stable.

(I)
In one aspect of the present invention, it relates to process for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) comprising the steps of:
i. treating the L-Ascorbic acid (IX) with acetone in methane sulfonic acid to provide 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one (VIII)

ii. oxidizing 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one (VIII) followed by reacting dimethyl sulphate to provide (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate (VII)

iii. reducing (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate (VII) in an organic solvent to get (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (VI)

iv. reacting (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (VI) with alkali iodate in basic medium in an organic solvent to form (S)-2,2-dimethyl-1,3- dioxolane-4-carbaldehyde (V)

v. (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (V) condensed with diethyl 2-oxoethyl phosphonate of formula (X) to get compound of formula (IV)

wherein R1 & R2 selected from C1-C5 alkyl, C1-C5 alkoxy with the proviso that both R1 and R2 may not be same, cycloalkyl, optionally substituted aryl or R1 and R2 combined together to form a C5-C8 cyclic ring.
v. reacting compound of formula (IV) with nitromethane and base in an organic solvent to get Nitro compound of formula (III);

vi. reducing compound of formula (III) into compound of formula (II);

vii. converting (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol (II) by reacting with base followed by acid reaction in alcohol to get (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I).

In another aspect of the present invention, compounds of formula (IV) and (III)

DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention provide an efficient process for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I). (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) obtained by the process of the present invention is found to be substantially pure.
In another embodiment according to present application, it provides a process for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I), comprising the steps of:
i. treating the L-Ascorbic acid (IX) with acetone in methane sulfonic acid to provide 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one (VIII);

ii. oxidizing 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one (VIII) followed by reacting dimethyl sulphate to provide (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate (VII);

iii. reducing (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate (VII) in an organic solvent to get (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (VI);

iv. reacting (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (VI) with alkali iodate in basic medium in an organic solvent to form (S)-2,2-dimethyl-1,3-
dioxolane-4-carbaldehyde (V);

v. (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (V) condensed with diethyl 2-oxoethyl phosphonate of formula (X) to get compound of formula (IV);

Wherein R1 & R2 selected from C1-C5 alkyl, C1-C5 alkoxy with the proviso that both R1 and R2 may not be same, cycloalkyl, optionally substituted aryl or R1 and R2 combined together to form a C5-C8 cyclic ring
v. reacting compound of formula (IV) with nitromethane and base in an organic solvent to get Nitro compound of formula (III);

vi. reducing compound of formula (III) into compound of formula (II);

vii. converting (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol (II) by reacting with base followed by acid reaction in alcohol to get (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I).

Individual steps of the embodiments are detailed herein below.
In process step of reacting L-Ascorbic acid (IX) with acetone in methane sulfonic acid to provide 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one (VIII) in a solvent at temperature ranging between 20-100°C for 3-10 hours.
In the process step ii of the present invention, oxidizing 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one (VIII) followed by reacting dimethyl sulphate to provide (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate (VII) in presence of base.
In the process step iii of the present invention, reducing (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate (VII) in an organic solvent to get (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (VI).
In the process step iv of the present invention, according to present invention reacting (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (VI) with alkali iodate in alkaline medium in an organic solvent to form (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (V).
In the process step v according to present invention, (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (V) condensed with diethyl 2-(diphenyl amino)-2-oxoethyl phosphonate of formula (X) to get compound of formula (IV).
In the process step vi according to present invention, compound of formula (IV) with nitromethane and base in an organic solvent to get Nitro compound of formula (III).
In the process step vii according to present invention, converting (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol (II) by reacting with base followed by acid reaction in alcohol to get (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I).
“Organic Solvent” as defined in the presence invention is selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone and/or mixtures thereof.
Suitable acid is selected from organic or inorganic acids. Preferably, the acid is selected from inorganic acids. More preferably, the acid is selected from sulfuric acid, hydrochloric acid and nitric acid.
“Base” as defined in the presence invention is selected from C1-6 alkyl amines, K2CO3, Na2CO3, NaHCO3, NH4OH, Mg(OH)2, CaCO3, Ca(OH)2, KOH, NaOH, NaH, KH, KOtBu, CH3COONa, CH3COOK, (CH3)3CONa, LiOH, TBAF (Tetra-n-butylammonium floride), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), TMG (1,1,3,3-tetramethyl-guanidine), N-Methylmorpholine and/or mixtures thereof.
Oxiding agents selected from Ozone (O3), Hydrogen peroxide (H2O2), Nitric acid (HNO3), Peroxydisulfuric acid (H2S2O8), Nitrous oxide (N2O), Peroxymonosulfuric acid (H2SO5).
Reducing agents selected from Lithium aluminium hydride (LiAlH4), mixture of LiCl and Sodium borohydride, Lindlar catalyst, Diborane, Sodium amalgam (Na(Hg)), Zinc amalgam (Zn(Hg)), Vitride , Diisobutylaluminium hydride (DIBAL-H), Hydrazine.
Alkali iodate are selected from sodium periodate or potassium periodate.
In one of the embodiment of the present invention R1 and R2 may be selected from C1-C5 alkyl, C1-C5 alkoxy with the proviso that both R1 and R2 may not be same, cycloalkyl, optionally substituted aryl or R1 and R2 combined together to form a C5-C8 cyclic ring.
In one of the particular embodiment, R1 and R2 is phenyl compound.
In one of the particular embodiment, process for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) comprising the steps of:
a. (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (V) condensed with diethyl 2-(diphenyl amino)-2-oxoethyl phosphonate of formula (XVI) to get (R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N,N-diphenylacrylamide (XIV);

b. reacting compound of (R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N,N-diphenyl acrylamide (XIV) with nitromethane and base in an organic solvent to get (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitro-N,N-diphenylbutanamide (XV);

c. reducing (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitro-N,N-diphenyl butanamide (XV) into (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol of (II);

d. converting (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol (II) by reacting with base followed by acid reaction in alcohol to get (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I).

In a preferred embodiment, the present invention provides the various methods for the purification of crude compounds, such as Filtration, Evaporation, Liquid–liquid extraction, solvent-anti solvent method, Crystallization, Recrystallization, Adsorption, Distillation, Fractionation, Sublimation, and Chromatography.
The invention was further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES:
Example 1: Synthesis of 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one
Methane sulfonic acid (6.5 mL, 0.10 mol) was added drop wise to a slurry of L-ascorbic acid (50 g, 0.283 mol) in acetone (125 mL) at 25-30oC. The mixture was stirred for 5h at 25-30°C. The precipitated product was filtered, washed with pre-cooled acetone (50 mL) and dried to obtain 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one (49 g) as a white solid.

Example 2: Preparation of (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate
To a suspension of 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one (44 g, 0.203 mol) in H2O (198 mL) was added 30% KOH (26.4 mL, 0.138 mol) at 25-30oC. The reaction mixture was stirred at 25-30o C until it became clear solution and NaHCO3 (42.6 g, 0.50 mol) was added. Then 35% aq. H2O2 (40 mL) was added drop wise over a period of 1 h. The reaction mixture was stirred for 2 h at 25-30oC, then sodium sulfite (3.08 g, 0.02 mol) and NaHCO3 (25.6 g, 0.30 mol) were added. The suspension was heated to 45oC and dimethyl sulfate (75.8 mL, 0.78 mol) was added drop wise within 4h, and the reaction mixture was stirred for another 12 h at 25-30°C. The reaction mixture was extracted with dichloromethane (4 x 250 mL). The combined organic phases were dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure to furnish (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate (37 g) as colorless liquid which was used in the next step without further purification.

Example 3: Preparation of (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol
To a stirred suspension of anhydrous lithium chloride (11.6 g, 0.274 mol) in methanol (100 mL) was added NaBH4 (10.2 g, 0.275 mol) at 0-5oC. The mixture was stirred at 0oC for 30-45 min and a solution of (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate (35g, 0.184 mol) in THF (250 mL) drop wise at 0-5oC. The reaction mixture was stirred overnight at room temperature and quenched with sat ammonium chloride (50 mL). Volatiles were evaporated under reduced pressure and aqueous phase extracted with 10% methanol/dichloromethane (5 x 100 mL). The combined organic layer was dried over anhydrous MgSO4 and evaporated under reduced pressure to afford (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (23.5 g) as a colorless oil.

Example 4: Preparation of (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde
A solution of (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (22 g, 0.135 mol) in tetrahydrofuran (220 mL) was added saturated NaHCO3 solution (8.43 mL) at 0° C. After 5-10min, NaIO4 (40.99 g, 0.191 mol) was added portion wise and allowed to stir at 15 to 20° C for 3-4h. After consumption of starting materials (by TLC), solid sodium sulfate (20 g) was added and the reaction mixture was stirred for further 15 min. The reaction mixture was diluted with diisopropylether (44 mL) and the reaction mixture was filtered. The filtrate was evaporated (below 25° C. bath temperature) to yield (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (16.5 g) as a colorless liquid.

Example 5: Preparation of (R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N,N-diphenyl acrylamide
To a stirred solution of diethyl 2-(diphenylamino)-2-oxoethylphosphonate (48 g, 0.138 mol) in THF (150 mL) was added (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (15 g, 0.115 mol) drop wise at 0°C. The solution was stirred for 5-10 min, then an aqueous solution of K2CO3 (47.7 g, 0.345 mol) in water (150 mL) was added drop wise. The resulting mixture was stirred for 16 h at 25-30°C. After consumption of starting materials, THF layer was separated and aqueous layer extracted with ethyl acetate (3 x 100 mL). The combined organic layer were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N,N-diphenylacrylamide (18.7 g).

Example 6: Preparation of (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitro-N,N-diphenylbutanamide
A mixture of (R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N,N-diphenylacrylamide (17.0 g, 0.052 mol) and acetonitrile (50 mL) was cooled to 0-5°C. Nitro methane (3.52 g, 0.0578 mol) followed by DBU (12.04 g, 0.0788 mol) were added to the reaction mixture at 0-5°C and stirred for 10-15 minutes at 0-5°C. The reaction mixture was warmed to 25-30oC and stirred for 16 h at the same temperature. The solvent from the reaction mixture was evaporated under reduced pressure. The reaction mixture was diluted with water (85 mL) and extracted with dichloromethane (6 x 85 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure get the (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitro-N,N-diphenylbutanamide (10g).

Example 7: Preparation of (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol
To a stirred solution of (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitro-N,N-diphenylbutanamide (1g, 0.002 mol) in THF (10 mL) was cooled to 0-5°C followed by addition of Vitride (0.526 g, 0.002 mol) at 0-5°C over a period of 5 minutes. The mixture was stirred at same temperature for 1 h. The progress of the reaction is monitored by TLC, additional amount of Vitride (0.263 g, 0.001 mol) was added to the mixture and stirred for additional 4 h. After consumption of starting material, reaction mixture was cooled to 0- 5°C and quenched with saturated sodium potassium tartrate solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was completely distilled under reduced pressure to afford the (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol (0.3 g) as colorless liquid.

Example 8: Preparation of (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol
To a stirred suspension of lithium aluminum hydride (0.148 g, 0.003 mol) in THF (5 mL) was added a solution of (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitro-N,N-diphenylbutanamide (1g, 0.002 mol) in THF (5 mL) at 0oC. The reaction mixture was warmed to 25-30oC and stirred at the same temperature for 1-2h. After consumption of starting material, the reaction mixture was quenched with ice cold water (5 mL) and diluted with ethyl acetate (10 mL). The layers are separated and organic layer dried over sodium sulfate and evaporated under reduced pressure to obtain the (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol (0.4 g) as viscous liquid.

Example 9: Preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol
To a stirred solution of (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol (2 g, 0.0091 mol) in isopropanol (16 mL) was added potassium tert-butoxide (1.43 g, 0.012 mol) portion wise at 25-30oC. The basic reaction mixture was added to a cooled solution of conc. HCl (2 mL) in IPA (16 mL) at 0-5oC drop wise. The reaction mixture was warmed to 25-30oC and stirred at the same temperature for 2-3h. After consumption of starting materials, triethylamine (1.83 g, 0.018 mol) was added and diluted with ethyl acetate. Filter the precipitated solids and filtrate was evaporated. Ethyl acetate was added to the residue and stirred for 15-20 min, filter the precipitated salts and evaporate the filtrate to obtain (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (0.5g). 1H NMR (CDCl3, 500 MHz): d 5.70 (d, J = 5.5 Hz, 1H), 4.48-4.42 (m, 1H), 4.02-3.96 (m, 2H), 3.94-3.88 (m, 1H), 3.65 (dd, J = 9.0, 6.9 Hz, 1H), 2.90-2.83 (m, 1H), 2.35-2.28 (m, 1H), 1.93-1.84 (m, 2H). Mass (m/z): 131.08 (M+1).

Example 10: Preparration of 2-Bromo-N, N-diphenyl acetamide
To a stirred solution of diphenylamine (4.87 g, 28.8 mmol) and pyridine (2.52 mL, 31.4 mmol) in 1,2-dichloroethane (40 mL) was added a solution of bromo acetyl bromide (2.5 mL, 30.0 mmol) in 1,2-dichloroethane (10 mL) at 0°C drop wise. After completion of the addition, the reaction mixture was warmed to 25-30°C and stirred for 1 h at 25-30°C. The reaction mixture was poured on ice water (100 mL) and acidified by addition of 2 M HCl. The reaction mixture was extracted with ethyl acetate (50 mL). The organic layer was separated, washed with water (100 mL), brine (100 mL)), dried over Na2SO4, filtered and evaporated in vacuo to provide 2-bromo-N,N-diphenyl acetamide (5.9 g) as off white solid. 1H NMR (CDCl3, 500 MHz): d 7.55-7.20 (m, 10 H), 3.84 (s, 2H); Mass (m/z): 291.9 (M+1).

Example 11: Synthesis of diethyl 2-(diphenylamino)-2-oxoethylphosphonate
To a stirred solution of 2-Bromo-N, N-diphenyl acetamide (5g, 0.017 mol) in 1,2-dichloroethane (50 mL) was added triethylphosphite (3.15g, 0.019 mol) at 25-30oC. The reaction mixture was refluxed for 8-10 h. After consumption of starting material, volatiles were evaporated under reduced pressure to obtain diethyl 2-(diphenylamino)-2-oxoethylphosphonate (5.1 g) which was used in the next step directly.

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
,CLAIMS:We Claim:
1. A process for preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) comprising the steps of:
i. treating the L-Ascorbic acid (IX) with acetone in methane sulfonic acid to provide 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one (VIII);

ii. oxidizing 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one (VIII) followed by reacting dimethyl sulphate to provide (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate (VII);

iii. reducing (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate (VII) in an organic solvent to get (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (VI);

iv. reacting (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (VI) with alkali iodate in basic medium in an organic solvent to form (S)-2,2-dimethyl-1,3- dioxolane-4-carbaldehyde (V)

v. (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (V) condensed with diethyl 2-oxoethyl phosphonate of formula (X) to get compound of formula (IV)

Wherein R1 & R2 selected from C1-C5 alkyl, C1-C5 alkoxy with the proviso that both R1 and R2 may not be same, cycloalkyl, optionally substituted aryl or R1 and R2 combined together to form a C5-C8 cyclic ring
v. reacting compound of formula (IV) with nitromethane and base in an organic solvent to get Nitro compound of formula (III);

vi. reducing compound of formula (III) into compound of formula (II);

vii. converting (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol (II) by reacting with base followed by acid reaction in alcohol to get (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I).

2. A process for preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I), according to claim 1, wherein the base selected from C1-6 alkyl amines, K2CO3, Na2CO3, NaHCO3, NH4OH, Mg(OH)2, CaCO3, Ca(OH)2, KOH, NaOH, NaH, KH, KOtBu, CH3COONa, CH3COOK, (CH3)3CONa, LiOH, TBAF (Tetra-n-butylammonium floride), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), TMG (1,1,3,3-tetramethyl-guanidine), N-Methylmorpholine and/or mixtures thereof.

3. A process for preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) according to claim 1, oxiding agents selected from Ozone (O3), Hydrogen peroxide (H2O2), Nitric acid (HNO3), Peroxydisulfuric acid (H2S2O8), Nitrous oxide (N2O), Peroxymonosulfuric acid (H2SO5).

4. A process for preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) according to claim 1, wherein reducing agents selected from Lithium aluminium hydride (LiAlH4), mixture of LiCl and Sodium borohydride, Lindlar catalyst, Diborane, Sodium amalgam (Na(Hg)), Zinc amalgam (Zn(Hg)), Vitride, Diisobutylaluminium hydride (DIBAL-H), Hydrazine.

5. A process for preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) according to claim 1, wherein organic solvent selected from water or alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or hydrocarbon solvents such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or esters solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or nitrile solvents such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or ether solvents such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or Amide solvents such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone and/or mixtures thereof.

6. A process for preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) according to claim 1, alkali iodate selected from the group consisting of sodium periodate or potassium periodate

7. A process for preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) according to claim 1, wherein preparation of diethyl 2-(diphenylamino)-2-oxoethylphosphonate (X) comprising the steps of:
a. reacting diphenyl amine with 2-bromoacetyl bromide in presence of a base in an organic solvent to get 2-bromo-N,N-diphenylacetamide

wherein R1 and R2 are defined previously in the claim.
b. reacting 2-bromo-N,N-acetamide compounds of formula (XI) with to Triethyl phosphite in an organic solvent to get diethyl -oxophosphonate compound of formula (X)

8. Compounds of formula (IV) and (III)

9. A process for preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I) according to claim 1, comprising the steps of:
a. (S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (V) condensed with diethyl 2-(diphenyl amino)-2-oxoethyl phosphonate of formula (XVI) to get (R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N,N-diphenylacrylamide (XIV);

b. reacting compound of (R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N,N-diphenyl acrylamide (XIV) with nitromethane and base in an organic solvent to get (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitro-N,N-diphenylbutanamide (XV);

c. reducing (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitro-N,N-diphenyl butanamide (XV) into (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol of (II);

d. converting (R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-ol (II) by reacting with base followed by acid reaction in alcohol to get (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (I).