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Intermediate for preparing eribulin and preparation method thereof

A compound and selected technology, applied in chemical instruments and methods, compounds of group 4/14 elements of the periodic table, organic chemistry, etc., can solve problems such as total synthesis is very difficult, and achieve easy quality control and refractory The effect of less impurities and easy post-processing

Active Publication Date: 2016-06-29
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with halichondrin B, eribulin has a smaller structure, but it also contains 19 chiral centers, and the total synthesis is also very difficult

Method used

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  • Intermediate for preparing eribulin and preparation method thereof
  • Intermediate for preparing eribulin and preparation method thereof
  • Intermediate for preparing eribulin and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 1

[0043] The synthesis of embodiment one F1

[0044] step 1:

[0045]

[0046] Compound F1-1 (1.17g) was dissolved in dry tetrahydrofuran (8ml), added tetrabutylammonium fluoride (563mg), reacted under nitrogen protection, TLC monitored the reaction was complete, added water (10ml), and then added ethyl acetate Extraction (15ml×3), combined organic phases, washed with saturated brine (50ml), dried over anhydrous magnesium sulfate, filtered, and spin-dried to obtain compound F1-2 (730mg).

[0047] MS:413[M+H] + .

[0048] Step 2:

[0049]

[0050] Compound F1-2 (730mg) was dissolved in dry dichloromethane (7ml), cooled to 0°C, added pyridine (419mg), DMAP (14mg) and PivCl (213mg) successively, stirred at room temperature for 1.5 hours under nitrogen protection, and used It was quenched with saturated ammonium chloride solution (10 ml). Then the organic layer was washed with water (10ml), saturated sodium bicarbonate solution (10ml) and saturated brine (10ml), dried ov...

Embodiment 2 2

[0052] The synthesis of embodiment two F2

[0053] step 1:

[0054]

[0055] SM2 (29g, 0.095mol) was dissolved in tetrahydrofuran (90ml), cooled to 10°C, LHMDS solution in THF (1M, 95.2ml) was added dropwise, and stirred at 10°C for half an hour. Subsequently, a toluene solution (140 ml) of compound F2-1 (35 g, 0.068 mol) was added dropwise, and the reaction was continued at 10° C. for half an hour after the drop was completed. The completion of the reaction was monitored by TLC. The reaction solution was washed with 1M aqueous hydrochloric acid (230ml) and saturated brine (175ml) successively, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude product F2-2 (60g).

[0056] MS:667[M+H] + .

[0057] Step 2:

[0058]

[0059]The crude compound F2-2 (60g) was dissolved in acetonitrile (200ml) and toluene (200ml), added TMSI (60ml), and reacted at 45°C for 2-4h. TLC monitors that the reaction is complete, the reac...

Embodiment 3 1

[0092] The synthesis of embodiment three E1

[0093]

[0094] Two Schlenk reaction vials (marked as 1 and 2) were pre-dried under an infrared lamp for 2-3 hours, then further dried with an alcohol torch under vacuum (vacuum oil pump), and then cooled to room temperature under vacuum.

[0095] Weigh CrCl in the glove box 2 (148mg), Liagnd4 (583mg), protonsponge (282mg) into Schlenk reaction flask 1, weigh Mn powder (220mg), NiCl 2 dmp (68mg), Compound F1 (992mg), Compound F2 (1.47g), LiCl (168mg), ZrCp 2 Cl 2 (876mg) was added to Schlenk reaction flask 2, and then the two reaction flasks were taken out, replaced in vacuum-argon 3 times, and then added CH 3 CN (5ml) to Schlenk reaction bottle 1, stirring reaction for 1-2 hours; Schlenk reaction bottle 2 is stand-by under the protection of argon;

[0096] The solution in the Schlenk reaction bottle 1 was transferred to the Schlenk reaction bottle 2 under the action of vacuum-argon with a double-ended needle, and then sti...

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Abstract

The invention provides an intermediate for preparing eribulin and a preparation method thereof. A novel intermediate is introduced into the eribulin synthesis route, which comprises more than 60 steps. The advantages of various routes in the prior art are integrated so as to industrially produce (macro-cyclic ketone) eribulin, which is difficult to synthesize.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an intermediate for preparing eribulin and a preparation method thereof. Background technique [0002] Halichondrin B (HalichondrinB) is a natural product with anti-tumor activity, which was originally isolated from the marine sponge Halichondriaokadai. Halichondrin B has 32 chiral centers, and its total synthesis is very difficult. [0003] Eribulin, as the first macrocyclic ketone analog obtained by optimizing the structure of halichondrin B, was first disclosed in CN1312804A, and it is currently prepared as Eribulin mesylate injection, which has been marketed in many countries for the treatment of metastatic breast cancer. Compared with halichondrin B, eribulin has a smaller structure, but it also contains 19 chiral centers, and its total synthesis is also very difficult. [0004] [0005] Therefore, there is a need to develop a synthetic method for preparing halichond...

Claims

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Application Information

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IPC IPC(8): C07F7/18C07D493/22
Inventor 林友刚蔡振伟朱益忠王善春郭猛张爱明
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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