Methods useful in the synthesis of halichondrin B analogs

Patent metadata

Field	Value
Publication number	US-9303039-B2
Application number	US-201414562086-A
Country	US
Kind code	B2
Filing date	Dec 5, 2014
Priority date	Dec 6, 2013
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

In general, the present invention features improved methods useful for the synthesis of analogs of halichondrin B, such as eribulin and pharmaceutically acceptable salts thereof (e.g., eribulin mesylate).

First claim

What is claimed is:

1. A method of preparing an intermediate in the synthesis of eribulin, said method comprising reacting a compound having formula (I):

wherein each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently a silyl group, with a fluoride source in a solvent comprising an amide to produce the intermediate ER-811475:

wherein the amide is an N,N C1-C6 dialkyl C1-C6 alkyl amide or N C1-C6 alkyl C2-C6 lactam.

2. The method of claim 1 , wherein the intermediate ER-811475 is produced in a mixture with an intermediate ER-811474:

3. The method of claim 2 , further comprising adding a mixture of acetonitrile and water.

4. The method of claim 1 , wherein each of R 1 , R 2 , R 3 , R 4 , and R 5 is t-butyldimethylsilyl.

5. The method of claim 1 , wherein the fluoride source is tetrabutylammonium fluoride.

6. The method of claim 1 , wherein the solvent further comprises tetrahydrofuran.

7. The method of claim 1 , wherein the amide is N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl 2-pyrrolidone, N,N-diethylacetamide, or N,N-dimethylpropionamide.

8. A method of producing eribulin, said method comprising the steps of:
a) producing an intermediate ER-811475:

by reacting a compound having formula (I):

wherein each of R 1 , R 2 , R 3 , R 4 , and R 5 is independently a silyl group, with a fluoride source in a solvent comprising an amide wherein the amide is an N,N C1-C6 dialkl C1-C6 alkyl amide or N C1-C6 alkyl C2-C6 lactam;
b) ketalizing intermediate ER-811475 to produce the intermediate ER-076349:

c) aminating ER-076349 to produce eribulin:

9. The method of claim 8 , further comprising salifying eribulin to produce a pharmaceutically acceptable salt of eribulin.

10. The method of claim 9 , wherein said salt is the mesylate salt.

11. The method of claim 8 , wherein ER-076349 is produced by reacting ER-811475 with a conjugate acid of imidazole.

12. The method of claim 8 , wherein step c) comprises converting ER-076349 to ER-082892:

by reacting ER-076349 with a sulfonylating reagent in the presence of a metal catalyst.

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Zhang Huiming
• Lewis Bryan M

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D493/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title