Compounds useful in the synthesis of halichondrin b analogs

Patent metadata

Field	Value
Publication number	US-2016376294-A1
Application number	US-201615196600-A
Country	US
Kind code	A1
Filing date	Jun 29, 2016
Priority date	Jan 26, 2010
Publication date	Dec 29, 2016
Grant date	—

Abstract

In general, the invention features compounds useful for the synthesis of analogs of halichondrin B, such as eribulin or pharmaceutically acceptable salts thereof, e.g., eribulin mesylate. Exemplary compounds are of formula (I), (II), or (III):

First claim

What is claimed is:

1 . (canceled)

2 . A compound having the formula:

wherein Q is —C(O)H, —CH═CHC(O)OY 1 , —C(R)H(CH2) n OY 1 , or —C(R)HCH 2 C(O)OY 1 ; R is H or —OY 2 ; n is 1 or 2; Y 1 , Y 2 , Y 3 , and Y 4 are each independently H or a hydroxyl protecting group; U is —OY 6 ; Y 5 is H or a hydroxyl protecting group or Y 5 , together with the oxygen atom to which it is bound, is a leaving group; and Y 6 is H or a hydroxyl protecting group or Y 5 , together with the oxygen atom to which it is bound, is a leaving group, provided that when Q is —(CH 2 ) 3 OY 1 , —OY 6 is a leaving group, and Y 1 , Y 3 , and Y 4 are protecting groups, Y 5 is not H, wherein Y 3 and Y 4 are each, independently and together with the oxygen atom to which it is bound, an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group, or Y 3 and Y 4 together with the oxygen atoms to which they are bound are a cyclic carbonate, cyclic boronate or cyclic silylene hydroxyl protecting group, or Y 3 and Y 4 together are acetal, ketal, or 1,1,3,3-tetraisopropylsiloxanediyl.

3 . The compound of claim 2 having the formula (IIIa):

4 . The compound of claim 2 , wherein Q is —(CH 2 ) 3 OY 1 .

5 . The compound of claim 4 , wherein Y 1 , together with the oxygen atom to which it is bound, is an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group; and Y 5 , together with the oxygen atom to which it is bound, is an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group.

6 . The compound of claim 5 , wherein Y 1 is pivaloyl, acetyl, benzoyl, p-bromobenzoyl, p-methoxybenzoyl, 1-naphthoyl, 2-naphthoyl, o-phthaloyl, benzyl, p-methoxybenzyl, triphenylmethyl, tri(C1-C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 heteroaryl)silyl, di(C6-C10 aryl or C1-C6 heteroaryl)(C1-C6 alkyl)silyl, or (C6-C10 aryl or C1-C6 heteroaryl)di(C1-C6 alkyl)silyl.

7 . The compound of claim 2 , wherein Y 3 and Y 4 are each independently tri(C1-C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 heteroaryl)silyl, di(C6-C10 aryl or C1-C6 heteroaryl)(C1-C6 alkyl)silyl, or (C6-C10 aryl or C1-C6 heteroaryl)di(C1-C6 alkyl)silyl, or Y 3 and Y 4 are together di(C1-C6)alkylsilylene.

8 . The compound of claim 5 , wherein Y 5 is acetyl, benzoyl, p-bromobenzoyl, p-methoxybenzoyl, 1-naphthoyl, 2-naphthoyl, or o-phthaloyl.

9 . The compound of claim 2 , wherein Y 5 is H or a hydroxyl protecting group.

10 . The compound of claim 2 , wherein Y 6 is H.

11 . The compound of claim 2 , wherein —OY 6 is a leaving group.

12 . The compound of claim 11 , wherein —OY6 is (C1-C6)alkylsulfonate, (C6-C10 aryl or C1-C6 heteroaryl)sulfonate, (C6-C15)aryl(C1-C6)alkylsulfonate, or (C1-C6)heteroaryl(C1-C6)alkylsulfonate.

13 . The compound of claim 12 , wherein —OY 6 is mesylate, toluenesulfonate, isopropylsulfonate, phenylsulfonate, or benzylsulfonate.

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Endo Atsushi
• Chase Charles E
• Fang Francis G

Classifications

• C07F7/1804 Primary

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• C07D307/12

  Radicals substituted by oxygen atoms · CPC title

• C07D405/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D407/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D307/38

  with substituted hydrocarbon radicals attached to ring carbon atoms · CPC title