PROCESS FOR PREPARATION OF ERIBULIN AND INTERMEDIATES THEREOF

Abstract

The present application relate to process for preparation of tetrahydrofuran compound of formula II, 4-Methylene tetrahydrofuran compound of formula V and tetrahydropyran compound of formula IX which are useful as intermediates for the preparation of halichondrin B analogues such as Eribulin or its pharmaceutically acceptable salts.

Claims

1. A process for preparation of tetrahydrofuran compound of formula II, ##STR00044## wherein P.sub.1, P.sub.2 and P.sub.3 are same or different alcohol protecting groups; which includes one or more of the following steps: (a) converting the compound of formula III to compound of formula IV, and ##STR00045## wherein P.sub.1, P.sub.2 and P.sub.3 is independently hydrogen or an alcohol protecting group; and (b) reducing the keto group of formula IV using suitable catalyst to provide compound of formula II ##STR00046## wherein P.sub.1, P.sub.2 and P.sub.3 are defined above.

2. The process according to claim 1, wherein the compound of formula II is ##STR00047##

3. The process according to claim 1, wherein the compound of formula III is ##STR00048##

4. The process according to claim 1, wherein the compound of formula IV is ##STR00049##

5. A process for the preparation of 4-Methylene tetrahydrofuran compound of formula V, ##STR00050## wherein P.sub.1 is H or an alcohol protecting group; P.sub.2 is H or an alcohol protecting group or SO.sub.2(R.sub.1); wherein R.sub.1 is selected from straight or branched C.sub.1-C.sub.10 alkyl or optionally substituted C.sub.5-C.sub.12 aryl; X is halogen; which process includes one or more of the following steps: (d) converting compound of formula VI to compound of formula VII; ##STR00051## wherein P is an alcohol-protecting group; R.sub.2, and R.sub.3 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkoxy, heteroalkyl, aryl, aralkyl, heteroaryl; all optionally substituted through available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, nitro, cyano, amino or substituted amino and the like or R.sub.2 and R.sub.3 together form a 4-7 membered ring containing a 1-3 heteroatoms selected from N, O, S wherein one or more carbon or hetero atoms of the 4-7 membered ring are optionally substituted with halo, alkyl, alkoxy, carbonyl, thiocarbonyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, nitro, cyano or amino; provided that when R.sub.2 is methyl, then R.sub.3 is not methoxy or when R.sub.3 is methyl, then R.sub.2 is not methoxy, wherein NR.sub.2R.sub.3 include; ##STR00052## or stereoisomers thereof; (e) converting compound of formula VII to compound of formula VIII; and ##STR00053## (f) converting compound of formula VIII to compound of formula V.

6. The process according to claim 5, wherein the compound of formula VI is ##STR00054##

7. A process for preparation of compound of formula IX, ##STR00055## wherein P.sub.1, P.sub.2 and P.sub.3 is an alcohol protecting group; which includes one or more of the following steps: (a) reacting compound of formula Va with compound of formula X to provide compound of formula XI; and ##STR00056## (b) converting compound of formula XI to compound of formula IX.

8. The process according to claim 7, wherein the compound of formula Va is ##STR00057## wherein Piv is Pivalovl.

9. A compound of formula Va or compound of formula Vb or compound of formula VII or compound of formula XI or compound of formula XIa or stereoisomers thereof ##STR00058## ##STR00059## wherein P, P.sub.1, P.sub.2 and P.sub.3 is same or different alcohol protecting group; and Piv is Pivalovl.

10. A process for preparation of eribulin or a pharmaceutically acceptable salt thereof from compound II of claim 1.

11. A process for preparation of eribulin or a pharmaceutically acceptable salt thereof from the compound of claim 5.

12. A process for preparation of eribulin or a pharmaceutically acceptable salt thereof from the compound o of claim 7.

Description

EXAMPLES

Example 1

Preparation of 1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-hydroxypropan-2-one

[0115] Acetic acid (13.2 mL) was added to the reaction mass containing (3aR,5R,6S,6aR)-5-allyl-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (10.2 g), acetone (306 mL) and water (62 mL) at 0 C. Solution containing potassium permanganate (11 g) in acetone (102 mL) and water (40 mL) was slowly added to the reaction mass at 0 C. and the resultant reaction mixture was stirred at 0 C. for 3 hours. Ethanol was added to the reaction mass at 5 C., filtered through the Celite bed and washed with ethyl acetate (60 mL). Filtrate concentrated under reduced pressure. The resultant filtrate was extracted with ethyl acetate (270 mL), the combined organic layer was washed with saturated sodium bicarbonate solution (3100 mL), brine solution (150 mL) and dried using sodium sulfate (50 g). The resultant organic layer concentrated in vacuo and purified using column chromatography to afford the title compound (5.7 g).

Example 2

Preparation of 3-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)propane-1,2-diol

[0116] Sodium borohydride (0.98 g) was added to the solution of 1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-hydroxypropan-2-one (5.6 g) in THF (56 mL) at 78 C. and the resultant reaction mixture was stirred at 78 C. for 4 hours. Reaction mixture was quenched with saturated NH.sub.4Cl solution (28 mL) at 50 C. and allowed to warm to room temperature for 30 minutes. Reaction mixture was extracted with ethyl acetate (242 mL) and the combined organic layers were washed with brine solution (128 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound (5.5 g; -isomer-28.34% and -isomer-68.68% by HPLC).

Example 3

Preparation of 3-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)propane-1,2-diol

[0117] (+) DIP-Cl (0.506 g, 1.6 M in Hexane) was added to a solution of 1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-hydroxypropan-2-one (0.35 g) in THF (8 mL) at 0 C. and the resultant reaction mixture was stirred at 30 C. for 24 hours. 10% NaOH (8 mL) and 20% H.sub.2O.sub.2 (8 mL) was added to the reaction mixture at 30 C. and stirred for 24 hours. Reaction mixture was extracted with ethyl acetate (310 mL), the combined organic layers were washed with brine solution (110 mL) and dried over Na.sub.2SO4. The resultant organic layer concentrated in vacuo and purified using column chromatography to afford the title compound (0.24 g; purity by HPLC: 94.87% /-isomer and 5.13% -isomer).

Example 4

Preparation of (S)-3-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)propane-1,2-diol

[0118] A buffer cocktail mixture consisting of KRED-101 (44 mg), NAD (20mg), CDX-901 (7.5 mg) and D-glucose (1.2 g) dissolved in 50mM potassium phosphate buffer, pH 8 (20 mL) was prepared. The resultant buffer cocktail mix was added to the solution of (3aR,5R,6S,6aR)-5-allyl-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (1.2 g 50 wt %) in toluene. The reaction mixture was continuously stirred at 25 C. and pH was maintained at 7 by periodic additions of 10wt % aqueous potassium carbonate solution via an auto-titrator for 19.5 hours. Reaction mixture was extracted with ethyl acetate (220 mL). The organic extracts were combined, dried over magnesium sulfate and solvent was removed under reduced pressure to afford title compound (Yield: 549 mg; de (diasteromeric excess) by HPLC=99.7%).

Example 5

Preparation of (S)-3-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)propane-1,2-diol

[0119] A buffer cocktail mixture consisting of CRED A631 (10 mg), NAD (20 mg), CDX-901 (8 mg) and D-glucose (1 g) dissolved in 50Mm potassium phosphate buffer, pH 8 (20 ml) was prepared. The buffer cocktail mixture was added to the (3aR,5R,6S,6aR)-5-allyl-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole in toluene (1.2 g of a 50 wt % solution), resultant reaction mixture was stirred at 25 C. for 24 hours and pH was maintained at 7.5 by periodic additions of 10wt % aqueous potassium carbonate solution. Reaction mixture was extracted with ethyl acetate (220 mL), the combined organic extracts were dried over magnesium sulfate and solvent was removed under reduced pressure to afford title compound.

Example 6

Preparation of (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-6-((2S,5S)-5-(3-((tert-butyld imethylsilyl)oxy)propyl)-3-methylenetetrahydrofuran-2-yl)-2-methyl hexanal

Preparation of Borane Ammonia Complex Solution/Suspension:

[0120] Borane ammonia complex (82 mg, 2.66 mmol) was added under a nitrogen atmosphere in a round-bottomed flask. This was then inerted via three evacuation/nitrogen re-fill cycles, tetrahydrofuran (1 mL) was charged under nitrogen and the suspension was maintained under a nitrogen atmosphere at 27 C.

[0121] n-Butyllithium (1.6 mL of a 1.6M solution in hexanes) was dropwise added to the solution containing tetrahydrofuran (1.5 mL) and diisopropylamine (373 l) at 75 C. and the resultant solution was stirred at 75 C. for 5 minutes, slowly warmed to 3 C. and stirred at 3 C. for 10 minutes. Borane ammonia suspension was added dropwise at 3 C. and stirred at 3 C. for 10 minutes. The solution was warmed to 27 C., stirred at 27 C. for 10 minutes and then cooled to 3 C. A solution of (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-N-((1 R,2R)-1-((tert-butyldimethylsilyl)oxy)-1-phenylpropan-2-yl)-6-((2S,5S)-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methylenetetrahydrofuran-2-yl)-N,2-dimethylhexanamide (270 mg) in tetrahydrofuran (2.5 mL) was added drop-wise under nitrogen atmosphere at 3 C. and the resultant reaction mixture was stirred for 17 hours at 27 C. MTBE (5 mL) was added under nitrogen followed by 1M hydrochloric acid (9 mL) and further MTBE (5 mL). The biphasic mixture was stirred for 1 hour and the phases separated. The aqueous phase was extracted with MTBE (10 mL). The combined organic extracts were washed with 1 M hydrochloric acid (35 mL), 1M sodium hydroxide (25mL), brine (10 mL), dried over MgSO.sub.4 and concentration in vacuo. The obtained crude alcohol compound was purified using flash column chromatography (123 mg, 71%).

[0122] The alcohol compound (60 mg) in a round-bottomed flask was inerted via three vacuum/nitrogen refill cycles and then charged with dichloromethane (1 mL). DMSO (170 l) and trimethylamine (170 l) was added and the resultant solution was cooled to 3 C. Pyridine-sulfur trioxide complex (76 mg) was added to the reaction mass at 3 C. and stirred for 19 hours whilst warming to 27 C. Saturated sodium bicarbonate solution (1 mL) and water (1 mL) were added followed by MTBE (10 mL). The phases were separated and the organic phase was washed with water (5 mL) and then brine (10 mL). The combined aqueous phases were extracted with MTBE (8 mL) and the combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The obtained crude compound was purified using flash column chromatography to afford title compound as colourless oil (45 mg, 75%) along with recovered alcohol compound (9 mg, 15%).

Example 7

Preparation of tert-butyl(3-((2S,5S)-5-((3R,5R)-3-((tert-butyldimethylsilyl)oxy)-5-methylhept-6-yn-1-yl)-4-methylenetetrahydrofuran-2-yl)propoxy)dimethylsilane

[0123] (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-6-((2S,5S)-5-(3-((tert-butyldimethylsilyl) oxy)propyl)-3-methylenetetrahydrofuran-2-yl)-2-methyl hexanal (43 mg) in a round-bottomed flask was inerted via nitrogen purge. Methanol (0.5 mL) was added and the solution was transferred under nitrogen to the reaction flask. Methanol (0.5 mL) was added under nitrogen atmosphere. Dimethyl (1-diazo-2-oxopropyl)phosphonate (500 mg of a 10% solution in acetonitrile) followed by potassium carbonate (27 mg, 0.20 mmol) was added to the reaction mass under a flow of nitrogen and the resultant reaction mixture was stirred for 19 hours. MTBE (15 mL) was added to the reaction mixture, washed with saturated sodium bicarbonate solution (5 mL) and brine (5 mL). The organic extract was dried over MgSO.sub.4 and concentrated in vacuo to provide the title compound (39 mg, 92%).

Example 8

Preparation of 3-((2S,5S)-5-((3R,5R)-6-iodo-5-methyl-3-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)hept-6-en-1-yl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate

[0124] N,N-dimethylpyridin-4-amine (0.947 g) was added to the solution containing 3-((2S,5S)-5-((3R,5R)-3-hydroxy-6-iodo-5-methylhept-6-en-1-yl)-4-methylenetetrahydro furan-2-yl)propyl pivalate (1.03 g) and dichloromethane (15.45 mL) at 5 C. Triethylamine (0.545 g) was added to the reaction mass at 5 C. 2,4,6-triisopropylbenzene-1-sulfonyl chloride (1.956 g) was added to the reaction mass at 5 C. and the resultant reaction mass was stirred at 28 C. for 16 hours. Water (5.15 mL) was added to the reaction mass at 28 C. and stirred at same temperature for 10 minutes. The phases were separated, organic phase was washed with saturated sodium bicarbonate solution (10.3 mL) and then saturated sodium chloride solution (5.15 mL) and the organic phase was concentrated in vacuo. Chased with heptane (5.15 mL). Heptane (10.m mL) was added and stirred for 10 minutes. Acetonitrile (10.3 mL) was slowly added and stirred for 5 minutes. Water (10.3 mL) was added and stirred for 5 minutes. The phases were separated, aqueous phase was extracted with heptane (5.15 mL) and the combined organic phase was washed with saturated sodium chloride solution (5.15 mL). The organic extract was dried over Na.sub.2SO.sub.4 and concentrated in vacuo to provide the title compound (1.46 g, 91%).

Example 9

Preparation of 3-((2S,5S)-5-((3R,5R,7R)-8-((2S,3S,4R,5R)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-methoxy-3-((phenylsulfonyl) methyl)tetrahydrofuran-2-yl)-7-hydroxy-5-methyl-6-methylene-3-(((2,4,6-triiso propylphenyl)sulfonyl)oxy)octyl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate

[0125] Chromium (II) chloride (0.924 g) was added to the reaction mixture containing (S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide (2.43 g) and anhydrous tetrahydrofuran (25 mL) at 28 C. in glove box. Triethylamine (0.768 g) was added dropwise to the reaction mass at 32 C. and stirred at 31-32 C. for 3 hours 30 minutes. Nickel (II) chloride (0.025 g) was added at 31 C. Solution containing 2-((2S,3S,4R,5R)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-methoxy-3-((phenyl sulfonyl)methyl)tetrahydrofuran-2-yl)acetaldehyde (0.67 g), 3-((2S,5S)-5-((3R,5R)-6-iodo-5-methyl-3-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)hept-6-en-1-yl)-4-ethylene tetrahydrofuran-2-yl)propyl pivalate (1.573 g) and tetrahydrofuran (15 mL) was added slowly to the reaction mixture at 31 C. and stirred at 31 C. for 16 hours. Ethylenediamine (1.3 g) was slowly added to the reaction mass at 4 C. and stirred at 0-2 C. for 1 hour. Water (10 mL) was added slowly at 10 C. and n-heptane (20 mL) followed by MTBE (20 mL) was added slowly to the reaction mass at 16 C. and stirred for 20 minutes. The phases were separated, aqueous phase was extracted with MTBE (230 mL) and the combined organic phase was washed with solution of sodium bicarbonate (1.0 g) and sodium chloride (3 g) in water (12 mL). The organic extract was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The resultant crude compound was chased with tetrahydrofuran (230 mL) and used for cyclization reaction (Next step).

Example 10

Preparation of 3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-methoxy-3-(phenylsulfonyl)methyl) tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl) ethyl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate

[0126] KHMDS (0.5 M in toluene) (20.5 mL) was added slowly to the reaction mass containing 3-((2S,5S)-5-((3R,5R,7R)-8-((2S,3S,4R,5R)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-methoxy-3-((phenylsulfonyl) methyl)tetrahydrofuran-2-yl)-7-hydroxy-5-methyl-6-methylene-3-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)octyl)-4-methylenetetra hydrofuran-2-yl)propyl pivalate (1.675 g) and tetrahydrofuran (40 mL) at 20 C. and stirred at 20 C. for 1 hour. Reaction mass was cannulated to solution of ammonium chloride (5.0g) in water (50 mL) at 8 C., MTBE (50 mL) was added and warmed to ambient temperature over 30 minutes. The phases were separated, aqueous phase was extracted with MTBE (230 mL) and the combined organic phase was washed with brine solution (30 mL). The organic extract was dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The obtained crude compound was subjected to Combiflash purification to afford title compound (0.52 g, 95.02% purity by HPLC).