DESC:The following specification particularly describes the invention and the manner in which it is to be performed

INTRODUCTION
Aspects of the present application relate to process for preparation of hexahydropyrano [3, 2-b] pyran compound of formula II, which is useful as an intermediate for the preparation of halichondrin B analogues such as Eribulin.
The drug compound having the adopted name Eribulin, is a synthetic analogue of halichondrin B, and is represented by structure of formula I.

I
Eribulin is a microtubule inhibitor indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. U.S. Patent No. 6,214,865 discloses eribulin and its pharmaceutically acceptable salts. Hexahydropyrano [3, 2-b] pyran compound of formula II used as an intermediate for the preparation of halichondrin B analogues such as Eribulin.

II
wherein P is an alcohol protected group and R is C1-C8 alkyl group
Process for the preparation of hexahydropyrano [3, 2-b] pyran compound of formula II have been disclosed in Tetrahedron Letters 49 (2008) 2939–2941. The reported processes suffer from major disadvantages, including use of highly expensive reagents, large amounts of catalysts, low temperature and longer reaction time. Hence, there remains a need to provide an alternative processes for the preparation of hexahydropyrano [3, 2-b] pyran compound of formula II, which is simple, economic and industrially viable.
SUMMARY
In an aspect, the present application relates to process for preparation of hexahydropyrano [3, 2-b] pyran compound of formula II, which includes one or more of the following steps:
(a) protecting the hydroxy furan compound of formula III with an alcohol- protecting group to provide compound of formula IV;

wherein P is an alcohol-protecting group;
(b) converting compound of formula IV to dihydroxy compound of formula V,

wherein P is an alcohol-protecting group;
(c) converting dihydroxy compound of formula V to aldehyde compound of formula VI;

wherein P is an alcohol-protecting group;
(d) treating aldehyde compound of formula VI with triphenyl phosphine compound of formula VII to provide compound of formula VIII;

wherein P is an alcohol protected group and R is C1-C8 alkyl group

(e) deprotecting the compound of formula VIII to provide hydroxy compound of formula IX;

wherein R is C1-C8 alkyl group
(f) converting compound of formula IX to compound of formula X;

wherein R is C1-C8 alkyl group
(g) protecting the hydroxy group of the compound of formula X with alcohol protecting group to provide compound of formula XI;

wherein P is an alcohol protected group and R is C1-C8 alkyl group
(h) reducing the keto group of formula XI to provide hydroxy compound of formula XII; and

wherein P is an alcohol protected group and R is C1-C8 alkyl group
(i) converting compound of formula XII to hexahydropyrano [3, 2-b] pyran compound of formula II.

DETAILED DESCRIPTION
In an aspect, the present application relates to process for preparation of hexahydropyrano [3, 2-b] pyran compound of formula II, which includes one or more of the following steps:
(a) protecting the hydroxy furan compound of formula III with an alcohol-
protecting group to provide compound of formula IV;

wherein P is an alcohol-protecting group;
(b) converting compound of formula IV to dihydroxy compound of formula V,

wherein P is an alcohol-protecting group;
(c) converting dihydroxy compound of formula V to aldehyde compound of formula VI;

wherein P is an alcohol-protecting group;
(d) treating aldehyde compound of formula VI with triphenyl phosphine compound of formula VII to provide compound of formula VIII;

wherein P is an alcohol protected group and R is C1-C8 alkyl group

(e) deprotecting the compound of formula VIII to provide hydroxy compound of formula IX;

wherein R is C1-C8 alkyl group
(f) converting compound of formula IX to compound of formula X;

wherein R is C1-C8 alkyl group
(g) protecting the hydroxy group of the compound of formula X with alcohol protecting group to provide compound of formula XI;

wherein P is an alcohol protected group and R is C1-C8 alkyl group
(h) reducing the keto group of formula XI to provide hydroxy compound of formula XII; and

wherein P is an alcohol protected group and R is C1-C8 alkyl group
(i) converting compound of formula XII to hexahydropyrano [3, 2-b] pyran compound of formula II.
Step (a) involves protecting the hydroxy furan compound of formula III with an alcohol- protecting group to provide compound of formula IV;
As used herein, "an alcohol protecting group" is a functional group that protects the alcohol group from participating in reactions that are occurring in other parts of the molecule. Suitable alcohol protecting groups that are used in step (a) include, acetyl, benzoyl, benzyl, ß-methoxyethoxymethyl ether, methoxymethyl ether, dimethoxytrityl, p-methoxybenzyl ether, methylthiomethyl ether, allyl ether, t-butyl ether, pivaloyl, trityl, silyl ether (e.g., trimethylsilyl (TMS), t-butyldimethylsilyl (TBMDS), t-. butyldiphenylsilyl (TBDPS), t-butyldimethylsilyloxymethyl (TOM) or triisopropylsilyl (TIPS) ether), tetrahydropyranyl (THP), methyl ether and ethoxyethyl ether (EE) or any suitable alcohol protecting group known in the art.
Suitable base that may be used in step (a) include, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide; carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide; organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole and the like or any other suitable base known in the art.
Suitable solvents that may be used in step (a) include ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane; and any mixtures of two or more thereof.
Suitable temperature that may be used in step (a) may be less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperature.
The reaction mixture obtained from step (a) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (a) may be isolated directly from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (b) or it may be isolated and further purified to improve the purity of the product.
Step (b) involves converting compound of formula IV to dihydroxy compound of formula V.
Suitable reagents that may be used in step (b) include osmium tetroxide, potassium permanganate, potassium dichromate, hydrogen peroxide, acetic acid, formic acid, t-butyl hydroperoxide and like or combination thereof or any other suitable reagents that are known in the art.
Suitable bases that may be used in step (b) include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide; carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide; organic bases, such as for example, N-methylmorpholine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, N-Methylmorpholine-N-oxide (NMO) and the like or any other suitable base known in the art.
Suitable solvents that may be used in step (b) include water, ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane; and any mixtures of two or more thereof.
Suitable temperature that may be used in step (b) may be less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperature.
The reaction mixture obtained from step (b) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (b) may be isolated directly from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (c) or it may be isolated and further purified to improve the purity of the product.
Step (c) involves converting dihydroxy compound of formula V to aldehyde compound of formula VI.
Suitable reagents that may be used in step (c) include sodium periodate, sodium (meta) periodate and like or any suitable reagents that are known in the art.
Suitable solvents that may be used in step (c) include ketones, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane; and any mixtures of two or more thereof.
Suitable temperature that may be used in step (c) may be less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperature.
The reaction mixture obtained from step (c) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (c) may be isolated directly from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (d) or it may be isolated and further purified to improve the purity of the product.
Step (d) involves treating aldehyde compound of formula VI with triphenyl phosphine compound of formula VII to provide compound of formula VIII;
Suitable solvents that may be used in step (d) include water, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane; and any mixtures of two or more thereof.
Suitable temperature that may be used in step (d) may be less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C, less than about -30°C, less than about -40°C, less than about -50°C, or any other suitable temperature.
The reaction mixture obtained from step (d) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (d) may be isolated directly from the reaction mixture itself after the reaction is complete in step (d), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (e) or it may be isolated and further purified to improve the purity of the product.
Step (e) involves deprotecting the compound of formula VIII to provide hydroxy compound of formula IX.
Suitable reagents that may be used in step (e) include acetic acid, formic acid, citric acid, tetra-n-butylammonium fluoride, copper (II) chloride dihydrate, boron trifluoride diethyl etherate, boron trifluoride dimethyl etherate and the like or combination thereof or any other suitable reagent known in the art.
Suitable solvents that may be used in step (e) include water, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane; and any mixtures of two or more thereof.
Suitable temperature that may be used in step (e) may be less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C or any other suitable temperature.
The reaction mixture obtained from step (e) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (e) may be isolated directly from the reaction mixture itself after the reaction is complete in step (e), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (f) or it may be isolated and further purified to improve the purity of the product.
Step (f) involves converting compound of formula IX to compound of formula X
Suitable solvents that may be used in step (f) include ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane; and any mixtures of two or more thereof.
Suitable temperature that may be used in step (f) may be less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C or any other suitable temperature.
The reaction mixture obtained from step (f) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (f) may be isolated directly from the reaction mixture itself after the reaction is complete in step (f), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (g) or it may be isolate as solid. The isolation in step (f) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.
Step (g) involves protecting the hydroxy group of the compound of formula X with alcohol protecting group to provide compound of formula XI
Suitable alcohol protecting groups that are used in step (g) include, acetyl, benzoyl, benzyl, ß-methoxyethoxymethyl ether, methoxymethyl ether, dimethoxytrityl, p-methoxybenzyl ether, methylthiomethyl ether, allyl ether, t-butyl ether, pivaloyl, trityl, silyl ether (e.g., trimethylsilyl (TMS), t-butyldimethylsilyl (TBMDS), t-. butyldiphenylsilyl (TBDPS), t-butyldimethylsilyloxymethyl (TOM) or triisopropylsilyl (TIPS) ether), tetrahydropyranyl (THP), methyl ether and ethoxyethyl ether (EE) or any suitable alcohol protecting group known in the art.
Suitable base that may be used in step (g) include, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide; carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide; organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole and the like or any other suitable base known in the art.
Suitable solvents that may be used in step (g) include ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane; and any mixtures of two or more thereof.
Suitable temperature that may be used in step (g) may be less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C, less than about -30°C, less than about -50°C, less than about -70°C, less than about -80°C, less than about -90°C or any other suitable temperature.
The reaction mixture obtained from step (g) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (g) may be isolated directly from the reaction mixture itself after the reaction is complete in step (g), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (h) or it may be isolated and further purified to improve the purity of the product.
Step (h) involves reducing the keto group of formula XI to provide hydroxy compound of formula XII.
Suitable reagents that may be used in step (h) include sodium borohydride, lithium aluminum hydride, sodium trimethoxy borohydride, Lithium borohydride, acetoxyborohydride, cyanoborohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, 9-borabicyclo(3.3.1)nonane (9-BBN), sodium dithionite or the like; or in combination with lithium bromide, aluminium chloride, zinc chloride, cobalt chloride or cerium chloride and the like or any other suitable reducing agent known in the art.
Suitable solvents that may be used in step (h) include water, ethers, alcohols, halogenated hydrocarbons, aromatic hydrocarbons or any mixtures of two or more thereof.
Suitable temperatures that may be used for the reaction of (h) may be less than about 130°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
The reaction mixture obtained from step (h) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (h) may be isolated directly from the reaction mixture itself after the reaction is complete in step (h), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (i) or it may be isolated and further purified to improve the purity of the product.
Step (i) involves converting compound of formula XII to hexahydropyrano [3, 2-b] pyran compound of formula II.
Suitable solvents that may be used in step (i) include ethers, halogenated hydrocarbons, aromatic hydrocarbons or any mixtures of two or more thereof.
Suitable temperatures that may be used for the reaction of (i) may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
The reaction mixture obtained from step (i) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (i) may be isolated directly from the reaction mixture itself after the reaction is complete in step (i), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like.
Optionally the compound obtained in steps (a) to (i) may be further purified by using purification techniques known in the art, for example using column chromatography or various types of isolation methods including recrystallization, slurry in solvent, crystallization by adding an anti-solvent to a solution and the like or any other suitable purification techniques known in the art.
Suitable solvents that may be used for the purification of the compound obtained in steps (a) to (i) include water, alcohols, ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane; and any mixtures of two or more thereof.
Optionally steps (a) to (i) or any two or more steps may be carried out as in-situ i.e. without isolating the intermediates in each stage.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions or the like.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol and the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of “C5-C8 aliphatic or aromatic hydrocarbons” include n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, and the like.
An “aromatic hydrocarbon solvent” refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has delocalized conjugated p system. Examples of an aromatic hydrocarbon solvent include benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C12 aromatic hydrocarbons and the like.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate and the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole and the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride and the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones and the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 Nitriles” include acetonitrile, propionitrile, butanenitrile and the like.
A “polar aprotic solvents” include N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone and the like;
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this application.
EXAMPLES
EXAMPLE 1: Preparation of (5R)-5-((tert-butyldimethylsilyl)oxy)-5-(furan-2-yl)pentane-1,2-diol. (R)-1-(furan-2-yl)pent-4-en-1-ol (5.6 g), dichloromethane (160 mL) and Imidazole (6.0 g) were charged into a round bottom flask at 27°C. Tert-Butyldimethylsilyl chloride (6.8 g) was slowly added to the reaction mixture at 27°C and the resultant reaction mixture was stirred at 27°C for 14 hours. Water (56 mL) was added to the reaction mixture and stirred for 10 minutes. Layers were separated, organic layer washed with water (56 mL) and dried with sodium sulfate (2.8 g). Organic layer solvent was distilled completely at below 45°C under reduced pressure. To the resultant compound, mixture of acetone and water (9:1; 180 mL) was added at 27°C and cooled to 0°C. Osmium tetroxide (0.02M; 4.4 mL) and N-Methylmorpholine-N-oxide (6.5 mL) was added to the reaction mixture at 0 °C and the resultant reaction mixture was stirred at 27°C for 4 hours. 10% sodium thiosulfate solution (56 mL) was added to the reaction mixture at 27°C and stirred for 15 minutes. Ethyl acetate (33 mL) was added to the reaction mixture and stirred for 15 minutes. Layers were separated; aqueous layer was extracted with ethyl acetate (2x33 mL) and combined organic layer washed with saturated sodium bicarbonate solution (33 mL) & 10% sodium chloride solution (33 mL). The resultant organic layer was dried with sodium sulfate and solvent was distilled completely at below 45 °C under reduced pressure. The obtained compound was further purified using column chromatography to afford title compound.
Yield: 9.2 g
EXAMPLE 2: Preparation of methyl (R, E)-6-((tert-butyldimethylsilyl)oxy)-6-(furan-2-yl)hex-2-enoate. (5R)-5-((tert-butyldimethylsilyl)oxy)-5-(furan-2-yl)pentane-1,2-diol (10.5 g) and dichloromethane (315 mL) was charged into a round bottom flask at 27°C. Sodium periodate on silica gel (36 g) was added to the reaction mixture at 27°C and the resultant reaction mixture was stirred at 27°C for 3 hours. Reaction mass was filtered, washed with dichloromethane (105 mL) and filtrate solvent was completely distilled at below 45°C under reduced pressure. To the resultant compound, dichloromethane (94 mL) and methyl 2-(triphenylphosphoranylidene) acetate (14.9 g) was added at 27°C and the resultant reaction mixture was stirred at 27°C for 4 hours. The resultant reaction mixture was absorbed with silica gel and purified by using column chromatography top afford title compound.
Yield: 8.7g
EXAMPLE 3: methyl (R, E)-6-(furan-2-yl)-6-hydroxyhex-2-enoate. Methyl (R,E)-6-((tert-butyldimethylsilyl)oxy)-6-(furan-2-yl)hex-2-enoate (5.8 g) and tetrahydrofuran (87 mL) charged into a round bottom flask at 27°C under nitrogen atmosphere and stirred for 10 minutes. Acetic acid (6.4 g) and tetra-n-butylammonium fluoride (14 g) was slowly added to the reaction mixture at 27°C and the resultant reaction mixture was stirred at 27°C for 63 hours under nitrogen atmosphere. Ethyl acetate (87 mL) and water (58 mL) was added to the reaction mixture and stirred for 10 minutes. Layers were separated, organic layer washed with water (58 mL), 10% sodium chloride solution (58 mL) and dried over sodium sulfate (2.9 g). The resultant organic layer solvent was distilled completely at below 45°C under reduced pressure. The obtained compound was purified using column chromatography to afford title compound.
Yield: 3.2g.
EXAMPLE 4: Preparation of methyl (E)-5-((2R)-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)pent-2-enoate. Vanadyl acetylacetonate (543 mg) and tert-butyl hydroperoxide (5.5 mL) was slowly added to the stirring solution of methyl (R, E)-6-(furan-2-yl)-6-hydroxyhex-2-enoate (4.8 g) in dichloromethane (72 mL) at 0°C and the resultant reaction mass was stirred at 25°C for 3 hours. Water (48 mL) was added to the reaction mass and stirred for 15 minutes. Layers were separated, aqueous layer extracted with dichloromethane (72 mL), combined organic layer washed with water (48 mL), 10% sodium chloride solution (48 mL) and dried over sodium sulfate (2.4 g). The resultant organic layer solvent was completely distilled at below 45°C under reduced pressure. The obtained compound was purified using column chromatography to afford title compound.
Yield: 3.0g
EXAMPLE 5: Preparation of (2S,6R)-6-((E)-5-methoxy-5-oxopent-3-en-1-yl)-5-oxo-5,6-dihydro-2H-pyran-2-yl benzoate. Methyl (E)-5-((2R)-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)pent-2-enoate (1.0 g), molecular sieves (1.0 g) and dichloromethane (30 mL) was charged into round bottom flask and stirred for 10 minutes. Triethylamine (1.33 g) was slowly added to the reaction mass at -78°C. Benzoyl chloride (0.61 g) was added to the reaction mass at -78°C and the resultant reaction mass was stirred at -78°C for 4 hours. Water (15 mL) was added to the reaction mass and stirred for 15 minutes. Reaction mass was filtered, washed with dichloromethane (20 mL). Filtrate layers were separated, organic layer was washed with water (15 mL), 10% sodium chloride solution (15 mL) and dried over sodium sulfate (1.0 g). The resultant organic layer was adsorbed on silica gel and purified by using column chromatography top afford title compound.
Yield: 400 mg
EXAMPLE 6: Preparation of (2S,4aR,6R,8aS)-6-(2-methoxy-2-oxoethyl)-2,4a,6,7,8,8a-hexahydropyrano[3,2-b]pyran-2-yl benzoate. (2S,6R)-6-((E)-5-methoxy-5-oxopent-3-en-1-yl)-5-oxo-5,6-dihydro-2H-pyran-2-yl benzoate (350 mg), dichloromethane (3.7 mL) and methanol (5.5 mL) was charged into round bottom flask under nitrogen atmosphere. Cerium chloride heptahydrate (0.372 g) and sodium borohydride (42 mg) was added to the reaction mass at -78°C under nitrogen atmosphere and the resultant reaction mass was stirred at -78°C for 2 hours. Water (3.7 mL) and dichloromethane (3.7 mL) was added to the reaction mass and stirred for 30 minutes. Reaction mass was filtered and washed with dichloromethane (3.7 mL). Filtrate layers were separated, organic layer washed with water (2x 3.7 mL), 10% sodium chloride solution (3.7 mL) and dried over sodium sulfate (0.17 g). The resultant organic layer solvent was distilled completely at below 45°C under reduced pressure. Tetrahydrofuran (5 mL) was added to the resultant compound and cooled to 0°C. Tetra-n-butylammonium fluoride (2 mL) was added to the reaction mass at 0°C and the obtained reaction mixture was stirred at 0°C for 45 minutes and at 30°C for 14 hours. Ethyl acetate (5 mL) and water (5 mL) was added to the reaction mass at 30°C and stirred for 15 minutes. Layers were separated, organic layer was washed with (3.7 mL), 10% sodium chloride solution (3.7 mL) and dried over sodium sulfate (0.17 g). The resultant organic layer solvent was distilled completely at below 45°C under reduced pressure. The obtained crude compound was further purified using column chromatography to afford title compound.
Yield: 150 mg
,CLAIMS:We Claim:

1. A process for preparation of hexahydropyrano [3, 2-b] pyran compound of formula II,

II
wherein P is an alcohol protected group and R is C1-C8 alkyl group
including one or more of the following steps:
(a) protecting the hydroxy furan compound of formula III with an alcohol-
protecting group to provide compound of formula IV;

wherein P is an alcohol-protecting group;
(b) converting compound of formula IV to dihydroxy compound of formula V,

wherein P is an alcohol-protecting group;
(c) converting dihydroxy compound of formula V to aldehyde compound of formula VI;

wherein P is an alcohol-protecting group;
(d) treating aldehyde compound of formula VI with triphenyl phosphine compound of formula VII to provide compound of formula VIII;

wherein P is an alcohol protected group and R is C1-C8 alkyl group
(e) deprotecting the compound of formula VIII to provide hydroxy compound of formula IX;

wherein R is C1-C8 alkyl group
(f) converting compound of formula IX to compound of formula X;

wherein R is C1-C8 alkyl group
(g) protecting the hydroxy group of the compound of formula X with alcohol protecting group to provide compound of formula XI;

wherein P is an alcohol protected group and R is C1-C8 alkyl group
(h) reducing the keto group of formula XI to provide hydroxy compound of formula XII; and

wherein P is an alcohol protected group and R is C1-C8 alkyl group
(i) converting compound of formula XII to hexahydropyrano [3, 2-b] pyran compound of formula II.

2. The process as claimed in claim 1, wherein alcohol protecting group is selected from acetyl, benzoyl, benzyl, methoxymethyl ether, t-butyldimethylsilyl (TBMDS), t-. butyldiphenylsilyl (TBDPS), t-butyldimethylsilyloxymethyl (TOM).

3. The process as claimed in claim 1, wherein alcohol protecting group is t-butyldimethylsilyl (TBMDS) or t-. butyldiphenylsilyl (TBDPS).

4. The process as claimed in claim 1, wherein R is selected from methyl, ethyl, propyl, isopropyl and tert-butyl.

5. The process as claimed in claim 1, wherein R is methyl or ethyl.