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Last Updated: October 22, 2019

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Claims for Patent: RE46965

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Summary for Patent: RE46965
Title:Intermediates for the preparation of analogs of Halichondrin B
Abstract: The present invention provides macrocyclic compounds, synthesis of the same and intermediates thereto. Such compounds, and compositions thereof, are useful for treating or preventing proliferative disorders Formula (F-4). ##STR00001##
Inventor(s): Austad; Brian (Tewksbury, MA), Chase; Charles E. (Londonderry, NH), Fang; Francis G. (Andover, MA), Calkins; Trevor (Stoughton, WI), Lewis; Bryan M. (North Brunswick, NJ)
Assignee: Eisai R&D Management Co., Ltd. (Tokyo, JP)
Application Number:13/924,892
Patent Claims: 1. A compound of formula F-4: ##STR00154## wherein: each of PG.sup.1, PG.sup.2, and PG.sup.3 is independently hydrogen or a suitable hydroxyl protecting group; R.sup.1 is R or --OR; each R is independently hydrogen, C.sub.1-4 haloaliphatic, benzyl, or C.sub.1-4 aliphatic; and LG.sup.1 is a suitable leaving group..].

.[.2. The compound according to claim 1, wherein said compound is of formula F-4': ##STR00155## .].

.[.3. The compound according to claim 2, wherein R.sup.1 is OR wherein R is hydrogen, methyl, or benzyl..].

.[.4. The compound according to claim 2, wherein PG.sup.1 and PG.sup.2 are both hydrogen..].

.[.5. The compound according to claim 2, wherein each of PG.sup.1 and PG.sup.2 is independently a suitable hydroxyl protecting group..].

.[.6. The compound according to claim 5, wherein one or both of PG.sup.1 and PG.sup.2, taken together with the oxygen atom to which each is bound, is a silyl ether or an arylalkyl ether..].

.[.7. The compound according to claim 6, wherein PG.sup.1 and PG.sup.2 are both t-butyldimethylsilyl..].

.[.8. The compound according to claim 5, wherein PG.sup.1 and PG.sup.2 are taken together, with the oxygen atoms to which they are bound, to form a diol protecting group..].

.[.9. The compound according to claim 8, wherein said diol protecting group is a cyclic acetal or ketal, a silylene derivative, a cyclic carbonate, or a cyclic boronate..].

.[.10. The compound according to claim 2, wherein LG.sup.1 is sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, or halogen..].

.[.11. The compound according to claim 10, wherein LG.sup.1 is mesyloxy tosyloxy, chloro, iodo, bromo, or triflate..].

.[.12. The compound according to claim 2, wherein said compound is: ##STR00156## .].

.[.13. The compound according to claim 1, wherein said suitable hydroxyl protecting group, taken with the oxygen atom to which it is bound, is selected from an ester, an ether, a silyl ether, an alkyl ether, an arylalkyl ether, and an alkoxyalkyl ether..].

.[.14. The compound according to claim 13, wherein said ester is a formate, acetate, carbonate, or sulfonate; said silyl ether is a trialkylsilyl ether; or said alkoxyalkyl ether is an acetal..].

.[.15. The compound according to claim 13, wherein said ester is formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, methyl carbonate, 9-fluorenylmethyl carbonate, ethyl carbonate, 2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-(phenylsulfonyl)ethyl carbonate, vinyl carbonate, ally! carbonate, or p-nitrobenzyl carbonate; said silyl ether is trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, or triisopropylsilyl ether; said alkyl ether is methyl, trityl, t-butyl, allyl, or allyloxycarbonyl ether; said alkoxyalkyl ether is methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers; or said arylalkyl ether is benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- picolyl, or 4-picolyl..].

.[.16. The compound according to claim 1, wherein LG.sup.1 is mesyloxy or tosyloxy..].

.[.17. The compound according to claim 9, wherein said cyclic acetal or ketal is methylene, ethylidene, benzylidene, isopropylidene, cyclohexylidene, or cyclopentylidene; or said silylene derivative is di-t-butylsilylene or a 1,1,3,3-tetraisopropyldisiloxanylidene derivative..].

.[.18. The compound according to claim 1, wherein LG.sup.1 is sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, or halogen..].

.Iadd.19. A compound of formula: ##STR00157## and/or a pharmaceutically acceptable salt thereof..Iaddend.

.Iadd.20. A composition comprising a compound: ##STR00158## and/or a pharmaceutically acceptable salt thereof, and a compound of formula: ##STR00159## and/or a pharmaceutically acceptable salt thereof..Iaddend.

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