Intermediates for the preparation of analogs of halichondrin B

Patent metadata

Field	Value
Publication number	US-RE47797-E
Application number	US-201815944480-A
Country	US
Kind code	E1
Filing date	Apr 3, 2018
Priority date	Jun 3, 2004
Publication date	Jan 7, 2020
Grant date	Jan 7, 2020

Abstract

Intermediates and methods of their use in the synthesis of analogs of halichondrin B are provided.

First claim

The invention claimed is:

1. A compound of formula F-2d:

wherein:
R′ is —CH═CH 2 or —C(O)H;
Alk is a C 1-4 straight or branched aliphatic group; and
PG 5 is a suitable hydroxyl protecting group.

2. The compound of claim 1 , wherein PG 5 , taken with the oxygen atom to which it is bound, is an ester, silyl ether, alkyl ether, arylalkyl ether, or alkoxyalkyl ether.

3. The compound of claim 1 , wherein PG 5 , taken with the oxygen atom to which it is bound, is a silyl ether.

4. The compound of claim 1 , wherein PG 5 is t-butyldimethylsilyl.

5. The compound of claim 1 , wherein Alk is methyl.

6. The compound of claim 1 of formula F-2d′:

7. The compound of claim 1 of formula:

8. A method of synthesizing a compound of formula F-2, the method comprising reacting a compound of formula F-2d:

wherein:
R′ is —CH═CH 2 or —C(O)H;
Alk is a C 1-4 straight or branched aliphatic group; and
PG 5 is a suitable hydroxyl protecting group
with a compound of formula F-2e:

wherein:
R″ is OH, OPG 3 , or LG 4 ;
LG 4 is a suitable leaving group; and
each PG 3 is independently a suitable hydroxyl protecting group
to produce a compound of formula F-2f:

 and
converting the compound of formula F-2f into the compound of formula F-2:

wherein:
each is independently a single or double bond, provided that both groups are not simultaneously a double bond;
LG 1 is a suitable leaving group;
X is halogen or —OSO 2 (R y );
R y is C 1-6 aliphatic or a 5-7 membered saturated, partially unsaturated, or fully unsaturated ring, wherein R y is optionally substituted with up to 3 groups selected from halogen, R, NO 2 , CN, OR, SR, or N(R) 2 ; and
each R is independently hydrogen, C 1-4 haloaliphatic, or C 1-4 aliphatic.

9. The method of claim 8 , wherein the compound of formula F-2 is

10. A method for preparing a compound of formula:

or a pharmaceutically acceptable salt thereof;
the method comprising producing the compound of formula B-1939 or a pharmaceutically acceptable salt thereof from a compound of formula F-2d:

wherein:
R′ is —CH═CH 2 or —C(O)H;
Alk is methyl; and
PG 5 is a suitable hydroxyl protecting group.

11. The method of claim 10, wherein PG 5 , taken with the oxygen atom to which it is bound, is an ester, silyl ether, alkyl ether, arylalkyl ether, or alkoxyalkyl ether.

12. The method of claim 10, wherein PG 5 , taken with the oxygen atom to which it is bound, is a silyl ether.

13. The method of claim 10, wherein PG 5 is t-butyldimethylsilyl.

14. The method of claim 10, wherein the compound of formula F-2d is of formula F-2d′:

15. The method of claim 10, wherein the compound of formula F-2d is of formula:

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Benayoud Farid
• Calkins Trevor Lee
• Chase Charles E
• Christ William
• Lewis Bryan M
• Schnaderbeck Matthew
• Pesant Marc
• Austad Brian
• Campagna Silvio
• Hu Yongbo
• Wilkie Gordon
• Zhu Xiaojie
• Fang Francis G

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07F7/188

  by reactions involving the formation of Si-O linkages · CPC title

• C07D493/18

  Bridged systems · CPC title

• C07D493/08

  Bridged systems · CPC title