DESC:INTRODUCTION
Aspects of the present application relate to process for preparation of hexahydropyrano [3, 2-b] pyran compound of formula IIIa, which is useful as an intermediate for the preparation of halichondrin B analogues such as Eribulin or its pharmaceutically acceptable salts.
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 IIIa used as an intermediate for the preparation of halichondrin B analogues such as Eribulin.

wherein R is –OR2 or NR3R4; wherein R2, R3 and R4 are same are different selected from hydrogen, optionally substituted C5-C12 aryl or straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl;
Process for the preparation of hexahydropyrano [3, 2-b] pyran compound of formula IIIa have been disclosed in Indian patent application no. 3529/CHE/2013 and Tetrahedron Letters 2008 Vol. 49, pp. 2939–2941. The reported processes suffer from major disadvantages, including low diastereoselectivity, cumbersome crystallization procedures, low temperature and use of column chromatography for purifications. Hence, there remains a need to provide an efficient process for the preparation of hexahydropyrano [3, 2-b] pyran compound of formula IIIa, which is simple, economic and industrially viable.
SUMMARY
In the first embodiment, the present application provides a process for preparation of hexahydropyrano [3, 2-b] pyran compound of formula IIIa,

wherein R is –OR2 or NR3R4; wherein R2, R3 and R4 are same are different selected from hydrogen, optionally substituted C5-C12 aryl or straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl; which includes one or more of the following steps:
(a) converting the compound of formula XVII to compound of formula XVIII;

wherein R is defined above; R1 is selected from straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl, or optionally substituted C5-C12 aryl;
(b) reducing the keto group of formula XVIII to provide hydroxy compound of
formula IXX; and

wherein R and R1 is defined above;
c) converting compound of formula IXX to hexahydropyrano [3, 2-b] pyran compound of formula IIIa.
In the second embodiment, the present application provides a process for preparation of compound of formula XVIII which comprising converting compound of formula XVII to compound of formula XVIII using (-)-levamisole or tetramisole derivatives as catalyst.

wherein R1 is selected from straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl, or optionally substituted C5-C12 aryl; R is –OR2 or NR3R4; wherein R2, R3 and R4 are same are different selected from hydrogen, optionally substituted C5-C12 aryl or straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl;
In the third embodiment, the present application provides a process for preparation of eribulin or a pharmaceutically acceptable salt thereof comprising synthesizing eribulin or its pharmaceutically acceptable salt from one or more compounds of first embodiment or second embodiment.

DETAILED DESCRIPTION
In the first embodiment, the present application provides a process for preparation of hexahydropyrano [3, 2-b] pyran compound of formula IIIa,

wherein R is –OR2 or NR3R4; wherein R2, R3 and R4 are same are different selected from hydrogen, optionally substituted C5-C12 aryl or straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl;
which includes one or more of the following steps:
(a) converting the compound of formula XVII to compound of formula XVIII;

wherein R is defined above; R1 is selected from straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl, or optionally substituted C5-C12 aryl;
(b) reducing the keto group of formula XVIII to provide hydroxy compound of
formula IXX; and

wherein R and R1 is defined above;
(c) converting compound of formula IXX to hexahydropyrano [3, 2-b] pyran
compound of formula IIIa.
Step (a) involves converting the compound of formula XVII to compound of formula XVIII;

wherein R is defined above; R1 is selected from straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl, or optionally substituted C5-C12 aryl;
Suitable catalysts that may be used in step (a) include levamisole, (S)-benzotetramisole, (S)-homobenzotetramisole ((S)-HBTM) and the like or any other chiral nucleophilic acylation catalysts that are known in the art.
Suitable solvents that may be used in step (a) include ethers, aliphatic and alicyclic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbon, nitriles, polar aprotic solvents, nitromethane or mixtures thereof.
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, the resulting product may be directly used for step (b) with or without isolation or it may be further purified, if isolated, to improve the purity of the product.
Step (b) involves reducing the keto group of formula XVIII to provide hydroxy
compound of formula IXX;

wherein R and R1 is defined above;
Suitable reagents that may be used in step (b) include sodium borohydride, lithium aluminum hydride, sodium trimethoxy borohydride, lithium borohydride, acetoxyborohydride, sodium cyanoborohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), (-)-B-chlorodiisopinocampheylborane, diisobutyl aluminium hydride, 9-borabicyclo(3.3.1)nonane (9-BBN), Corey-Bakshi-Shibata catalyst, 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, alcohols, ethers, halogenated hydrocarbons, aromatic hydrocarbons or any mixtures of two or more thereof.
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, the resulting product may be directly used for step (c) with or without isolation or it may be further purified, if isolated, to improve the purity of the product.
Step (c) involves converting compound of formula IXX to hexahydropyrano [3, 2-b] pyran compound of formula IIIa.
Compound of formula IXX to hexahydropyrano [3, 2-b] pyran compound of formula IIIa may be converted by:
(a) converting compound of formula IXX to provide compound of formula XX;

(b) deprotecting compound of formula XX to provide compound of formula X;
and

wherein R and R1 is defined above;
(c) oxidizing compound of formula XX to provide compound of formula IIIa.
In the second embodiment, the present application provides a process for preparation of compound of formula XVIII which comprises converting compound of formula XVII to compound of formula XVIII using (-)-levamisole or tetramisole derivatives as catalyst.

wherein R1 is selected from straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl, or optionally substituted C5-C12 aryl; R is –OR2 or NR3R4; wherein R2, R3 and R4 are same are different selected from hydrogen, optionally substituted C5-C12 aryl or straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl;
Suitable catalysts that may be used in step (a) include levamisole, (S)-benzotetramisole, (S)-homobenzotetramisole ((S)-HBTM) and the like or any other chiral nucleophilic acylation catalysts that are known in the art.
Suitable solvents that may be used for the converting compound of formula XVII to compound of formula XVIII include ethers, aliphatic and alicyclic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbon, nitriles, polar aprotic solvents, nitromethane or mixtures thereof.
The reaction obtained mixture 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 compound of formula XVIII may be isolated directly from the reaction mixture itself after the reaction is complete, or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, the resulting product may be directly used for next step with or without isolation or it may be further purified, if isolated, to improve the purity of the product.
In the third embodiment, the present application provides a process for preparation of eribulin or a pharmaceutically acceptable salt thereof comprising synthesizing eribulin or its pharmaceutically acceptable salt from one or more compounds of first embodiment or second embodiment.
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.
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 the present application 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 used for protecting alcohols.
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, cyclohexanol, phenol, glycerol, 2-methoxyethanol, 2-ethoxyethanol 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 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, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, 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 (E)-methyl 5-((2S)-6-(isobutyryloxy)-3-oxo-3,6-dihydro-2H-pyran-2-yl)pent-2-enoate.
Levamisole (45 mg) was added to the reaction mass containing (E)-methyl 5-((2S)-6-hydroxy-3-oxo-3,6-dihydro-2Hpyran-2-yl)pent-2-enoate (1 g), toluene (20 mL) and molecular sieves (1 g) at 27 °C under nitrogen atmosphere. Diisopropylethylamine (1.14 g) was slowly added to the reaction mass at 27 °C and stirred for 5 minutes. Isobutyric anhydride (1.05 g) was added lot wise (six lots) to the reaction mass at 28 °C over a period of 5 hours. The resultant reaction mass was filtered, washed with toluene (10 mL). Water (10 mL) was added to the filtrate and stirred for 10 minutes. The layers were separated and aqueous layer extracted with toluene (10 mL). The combined organic layer washed with water (3x10 mL), 10% sodium chloride solution (10 mL) and the resultant organic layer was concentrated in vacuo to afford the titled product (ß-Isomer: 92.5%).
EXAMPLE 2: Preparation of (E)-methyl 5-((2S,3R,6S)-3-hydroxy-6-(isobutyryloxy)-3,6-dihydro-2Hpyran-2-yl)pent-2-enoate:
Cerium chloride heptahydrate (5.02 g) was added to the reaction mass containing (E)-methyl 5-((2S,6S)-6-(isobutyryloxy)-3-oxo-3,6-dihydro-2H-pyran-2-yl)pent-2-enoate (4.0 g), methyl tert-butyl ether (15 mL) and methanol (10 mL) at -70 °C and stirred for 10 minutes. Sodium borohydride (0.153 g) was added to the reaction mass at -70 °C and stirred at -70 °C for 1 hour 30 minutes. Ethyl acetate (5 mL) and water (10 mL) was slowly added to the reaction mass at -15 °C. Filtered the reaction mass, washed with ethyl acetate (20 mL) and filtrate layers were separated. The aqueous layer extracted with ethyl acetate (20 mL), combined organic layer washed with water (3x10 mL), 10% sodium chloride solution (10 mL) and the resultant organic layer was concentrated in vacuo to afford the titled product (4.02 g).
EXAMPLE 3: Preparation of (2S,4aR,6R,8aS)-6-(2-methoxy-2-oxoethyl)-2,4a,6,7,8,8ahexahydropyrano[3,2-b]pyran-2-yl isobutyrate:
Tetra-n-butylammonium fluoride (1.753 g 1M in THF) was slowly added to the reaction mass containing (E)-methyl 5-((2S,3R,6S)-3-hydroxy-6-(isobutyryloxy)-3,6-dihydro-2H-pyran-2-yl)pent-2-enoate(1 g) and tetrahydrofuran (50 mL) at 28 °C under nitrogen atmosphere and the resultant reaction mixture was stirred at 28 °C for 5 hours. Ethyl acetate (20 mL) and water (10 mL) was slowly added to the reaction mass and stirred for 5 minutes. The layers were separated, aqueous layer extracted with ethyl acetate (20 mL), combined organic layer washed with sodium bicarbonate solution (3x10 mL), water (10 mL), 20% sodium chloride solution (10 mL) and the resultant organic layer was concentrated in vacuo to afford the titled product.
EXAMPLE 4: Preparation of methyl 2-((2R,4aS,6R,8aR)-6-hydroxy-2,3,4,4a,6,8ahexahydropyrano[3,2-b]pyran-2-yl)acetate :
((2S,4aR,6R,8aS)-6-(2-methoxy-2-oxoethyl)-2,4a,6,7,8,8ahexahydropyrano [3,2-b]pyran-2-yl isobutyrate (1.0g), methanol (4.5 mL), water (0.5 mL) and Amberlite IR 400 Cl form (0.1 g) charged into a round bottom flask. The resultant reaction mixture was heated to 63 °C and stirred at 63°C for 6 hours. The reaction mass was filtered and washed with acetone (5 mL). Filtrate was concentrated in vacuo and chased with acetone (10 mL) to afford the titled product.

Dated: 3rd day of November 2017 Signature:_______________
(Dr. Poonam Raghuvanshi)

CLAIMS
We claim:
1. A process for preparation of hexahydropyrano [3, 2-b] pyran compound of formula IIIa,

wherein R is –OR2 or NR3R4; wherein R2, R3 and R4 are same are different selected from hydrogen, optionally substituted C5-C12 aryl or straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl; which includes one or more of the following steps:
(a) converting the compound of formula XVII to compound of formula XVIII;

wherein R is defined above; R1 is selected from straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl, or optionally substituted C5-C12 aryl;
(b) reducing the keto group of formula XVIII to provide hydroxy compound of
,CLAIMS:CLAIMS
We claim:
1. A process for preparation of hexahydropyrano [3, 2-b] pyran compound of formula IIIa,

wherein R is –OR2 or NR3R4; wherein R2, R3 and R4 are same are different selected from hydrogen, optionally substituted C5-C12 aryl or straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl; which includes one or more of the following steps:
(a) converting the compound of formula XVII to compound of formula XVIII;

wherein R is defined above; R1 is selected from straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl, or optionally substituted C5-C12 aryl;
(b) reducing the keto group of formula XVIII to provide hydroxy compound of
formula IXX; and
wherein R and R1 is defined above;
c) converting compound of formula IXX to hexahydropyrano [3, 2-b] pyran compound of formula IIIa.
2. The process of claim 1, wherein compound of formula XVII is converted to compound of formula XVIII in step (a) using a catalyst selected from levamisole or (S)-benzotetramisole or (S)-homobenzotetramisole ((S)-HBTM)

3. The process of claim 1, reducing agent used in step (b) is Sodium borohydride.

4. A process for preparation of compound of formula XVIII which comprising converting compound of formula XVII to compound of formula XVIII using (-)-levamisole or tetramisole derivatives as catalyst.

wherein R1 is selected from straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl, or optionally substituted C5-C12 aryl; R is –OR2 or NR3R4; wherein R2, R3 and R4 are same are different selected from hydrogen, optionally substituted C5-C12 aryl or straight or branched C1-C10 alkyl optionally substituted with C5-C12 aryl;
5. A process for preparation of eribulin or a pharmaceutically acceptable salt thereof comprising synthesizing eribulin or its pharmaceutically acceptable salt from one or more compounds of claim 1 or claim 4.