Synthesis of eribulin mesylate

Abstract

A preparation method of an intermediate compound of formula II ((1R,2S,3S,4S,5S,6R,11S,14S,17S,19R,21R,23S,25R,26R,27S,31R,34S)-25-[(2S)-2,3-dihydroxy]-2,5-dihydroxy-26-methoxy-19-methyl-13,20-dimethylene-24,35,36,37,38,39-hexaoxane[29.3.1.1.sup.3,6.1.sup.4,34.11.sup.1,14.1.sup.17,21.0.sup.23,27]nonatriacontan-8,29-dione) for eribulin mesylate is provided, including subjecting a compound of formula I to a reaction with an additive in the presence of tetra-n-butylammonium fluoride (TBAF). The additive is piperidine hydrochloride or pyridine hydrochloride, and a reaction formula is as follows: ##STR00001## The present invention aims to avoid the problem that a traditional synthetic route has a low yield.

Claims

1. A preparation method of an intermediate compound of formula II ((1R,2S,3S,4S,5S,6R,11S,14S,17S,19R,21R,23S,25R,26R,27S,31R,34S)-25-[(2S)-2,3-dihydroxy]-2,5- dihydroxy-26-methoxy-19-methyl-13,20-dimethylene-24,35,36,37,38,39-hexaoxane [29.3.1.1.sup.3,6.1.sup.4,34.11.sup.1,14.1.sup.17,21.0.sup.23,27]nonatriacontan-8,29-dione) for eribulin mesylate, comprising: subjecting a compound of formula I (2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[(2R ,3R,3aS,7R,10S,11S,12S,13R,14S,15S,16E,21 S,24S,27S,29R,31R,32aS)-12,13,15-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3a,4,5,6,7,8,9,10,11,12,13,14,15,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,32a- triahydro-3-methoxy-29-m ethyl-23,30-bis(methylene)-5,18-dioxo-7,11:10,14:21,24:27,31-tetraepoxy-2H-cyclohentriaconta ne[b]furan-2-yl]propyl]-1-[(1,1-dimethylethyl)dimethylsilyl]ether) to a reaction with an additive in the presence of tetra-n-butylammonium fluoride (TBAF), wherein the additive is piperidine hydrochloride or pyridine hydrochloride, and a reaction formula is as follows: ##STR00010##

2. The preparation method according to claim 1, wherein the TBAF is used at a molar equivalent 5 to 20 times a molar equivalent of the compound of formula I.

3. The preparation method according to claim 1, wherein the piperidine hydrochloride or the pyridine hydrochloride is used at a molar equivalent 3 to 10 times a molar equivalent of the compound of formula I.

4. The preparation method according to claim 1, wherein the reaction is conducted at 0° C. to 30° C.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

(1) The present disclosure is illustrated below through typical examples, and simple replacements and improvements made by those skilled in the art to the present disclosure are all within the technical solutions claimed by the present disclosure.

Example 1 Preparation of a compound of formula II (using piperidine hydrochloride) (with a yield of 85%)

(2) ##STR00006##

(3) The compound of formula I (460.0 mg, 0.348 mmol) was dissolved in THF (21.5 mL) at 20° C. to 25° C., then piperidine hydrochloride (211.6 mg, 1.74 mmol) and TBAF (1 M THF solution, 3.48 mL, 3.48 mmol) were added, and a resulting reaction solution was stirred at the temperature for 20 h. The reaction solution was concentrated under reduced pressure at 30° C. to remove THF and then dissolved in a small amount of DCM, and then the target compound was purified and collected by column chromatography (EA/n-Hept=1/1.fwdarw.EA.fwdarw.MeOH/EA=1/15) to obtain the compound of formula II (white solid, 222.3 mg, 85.3%), ESI-MS: C.sub.40H.sub.60O.sub.13: calculated value: 748.4034, measured value: 749.4065 (M+H.sup.+)..sup.1H NMR (600 MHz, CDCl.sub.3)

(4) 5.00 (1H, brd, J=1.8 Hz), 4,85 (1H, brd, J=1.8 Hz), 4.88 (1H, brs), 4.80 (1H, brd, J=1.2 Hz), 4.48-4.54 (1H, m), 4.38 (1H, dd, J.sub.1=9.0 Hz, J.sub.2=4.2 Hz), 4.34 (1H, dt, J.sub.1=10.2 Hz, J.sub.2=3.6 Hz), 3.97-4.09 (5H, m), 3.94-3.99 (1H, m), 3.85-3.94 (3H, m), 3.78-3.85 (1H, m), 3.74 (1H, dd, J.sub.1=9.6 Hz, J.sub.2=1.8 Hz), 3.64 (1H, dd, J.sub.1=11.4 Hz, J.sub.2=3.6 Hz), 3.50-3.58 (1H, m), 3.40-3.46 (1H, m), 3.28-3.34 (1H, m), 3.30 (3H, s), 3.19 (1H, dd, J.sub.1=15.0 Hz, J.sub.2=10.2 Hz), 2.72-2.85 (2H, m), 2.49-2.69 (5H, m), 2.28-2.37 (2H, m), 2.14-2.30 (3H, m), 2.05-2.12 (1H, m), 1.98-2.05 (1H, m), 1.89-1.99 (2H, m), 1.64-1.81 (5H, m), 1.34-1.64 (5H, m), 1.03-1.13 (1H, m), 1.06 (3H, J=6.0 Hz). .sup.13C NMR (150 MHz, CDCl3) 209.95, 208.71, 150.64, 149.04, 106.10, 104.85, 87.49, 82.53, 79.79, 79.57, 77.59, 77.40, 77.17, 76.83, 76.43, 75.97, 75.24, 73.57, 73.38, 71.08, 66.62, 65.80, 65.38, 56.94, 48.67, 47.91, 43.58, 42.89, 41.10, 40.93, 39.09, 37.71, 35.67, 32.57, 30.66, 30.51, 30.41, 30.09, 29.64, 17.89.

Example 2: Preparation of a compound of formula II (using pyridine hydrochloride) (with a yield of 89%)

(5) ##STR00007##

(6) The compound of formula I (460.0 mg, 0.348 mmol) was dissolved in THF (21.5 mL) at 20° C. to 25° C., then pyridine hydrochloride (201.1 mg, 1.74 mmol) and TBAF (1 M THF solution, 3.48 mL, 3.48 mmol) were added, and a resulting reaction solution was stirred at the temperature for 20 h. The reaction solution was concentrated under reduced pressure at 30° C. to remove THF and then dissolved in a small amount of DCM, and then the target compound was purified and collected by column chromatography (EA/n-Hept=1/1.fwdarw.EA.fwdarw.MeOH/EA=1/15) to obtain the compound of formula II (white solid, 232.1 mg, 88.9%).

Example 3: Preparation of a compound of formula II (comparative experiment, using only TBAF) (with a yield of 38%)

(7) ##STR00008##

(8) The compound of formula I (460.0 mg, 0.348 mmol) was dissolved in THF (21.5 mL) at 20° C. to 25° C., then TBAF (1 M THF solution, 3.48 mL, 3.48 mmol) was added, and a resulting reaction solution was stirred at the temperature for 20 h. The reaction solution was concentrated under reduced pressure at 30° C. to remove THF and then dissolved in a small amount of DCM, and then the target compound was purified and collected by column chromatography (EA/n-Hept=1/1.fwdarw.EA.fwdarw.MeOH/EA=1/15) to obtain the compound of formula II (white solid, 99.7 mg, 38.2%).

Example 4: Preparation of a compound of formula II (comparative experiment, using imidazole hydrochloride) (with a yield of 50%)

(9) ##STR00009##

(10) The compound of formula 1 (460.0 mg, 0.348 mmol) was dissolved in THF (21.5 mL) at 20° C. to 25° C., then imidazole hydrochloride (181.9 mg, 1.74 mmol) and TBAF (1 M THF solution, 3.48 mL, 3.48 mmol) were added, and a resulting reaction solution was stirred at the temperature for 20 h. The reaction solution was concentrated under reduced pressure at 30° C. to remove THF and then dissolved in a small amount of DCM, and then the target compound was purified and collected by column chromatography (EA/n-Hept=1/1.fwdarw.EA.fwdarw.MeOH/EA=1/15) to obtain the compound of formula II (white solid, 131.5 mg, 50.4%).