Intermediates and methods for the synthesis of halichondrin B analogs
AssigneeEisai R&D Management Co., Ltd.
InventorsCharles Chase, Atsushi Endo, Frances G. Fang, Jing Li
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Abstract
Methods of synthesizing intermediates useful for the synthesis of halichondrin B analogs are described.
Claims39
A method of obtaining a substantially diastereomerically pure composition of a compound of formula (I), comprising:
- crystallizing said compound of formula (I) from a mixture of diastereomers under appropriate crystallization conditions, wherein said compound of formula (I) is:
- wherein:
- z is a single or double bond, provided that when z is a double bond, X2 is C and Y1 is hydrogen;
- and provided that when z is a single bond, X2 is CH or O;
- X1 is O, S, or CN, provided that when X1 is CN or S, X2 is O;
- Y1 is a halide, hydrogen or O-L2, or absent when X2 is O;
- L1 and L2 are independently selected from hydrogen and a protecting group, or L1 and L2 together are a protecting group, provided that when X1 is CN, L1 is absent;
- or a salt thereof.
A method of making a substantially diastereomerically pure composition of a compound of formula (Ib) from a compound of formula (Ia), wherein the compound of formula (Ia) is:
- and the compound of formula (Ib) is:
- wherein L1a and L1b are independently selected from hydrogen and a protecting group, or L1a and L1b together are a divalent protecting group, provided that L1a of formulae (Ia) and (Ib) are the same and L1b of formulae (Ia) and (Ib) are the same, said method comprising:
- reacting the compound of formula (Ia) under alkylating conditions to form a mixture comprising the compound of formula (Ib) and diastereomers thereof;
- and
- crystallizing the compound of formula (Ib) from the mixture, under appropriate crystallization conditions.
A method of obtaining a substantially diastereomerically pure composition of a compound of formula (II), comprising:
- crystallizing said compound of formula (II) from a mixture of diastereomers under second appropriate crystallization conditions, wherein said compound of formula (II) is:
- wherein:
- c is a single or double bond, provided that when c is a double bond m is 0 and Y3 is O or CHCO2-L3, and provided that when c is a single bond, m is 0 or 1, Y3 is CH2O-L3, CH2CO2-L3 or CH2CH2O-L3;
- Y2 is C1-C7 sulfonate, O-L4 or a halide;
- L4 is hydrogen or a protecting group;
- and
- L3 and L5 are each independently hydrogen or a protecting group, or L3 and L5 together are a protecting group;
- or a salt thereof.
A compound of formula (I):
- wherein:
- z is a single or double bond, provided that when z is a double bond, X2 is C and Y1 is hydrogen;
- and provided that when z is single bond, X2 is CH or O;
- X1 is O, S, or CN, provided that when X1 is CN or S, X2 is O;
- Y1 is a halide, hydrogen or O-L2, or absent when X2 is O;
- and
- L1 and L2 are independently selected from hydrogen and a protecting group, or L1 and L2 together are a protecting group, provided that when X1 is CN, L1 is absent;
- or a salt thereof.
A compound of the formula (II):
- wherein:
- c is a single or double bond, provided that when c is a double bond, m is 0, and Y3 is O or CHCO2-L3, and provided that, when c is a single bond, m is 0 or 1, and Y3 is CH2O-L3, CH2CO2-L3 or CH2CH2O-L3;
- Y2 is C1-C7 sulfonate, O-L4 or a halide;
- L4 is hydrogen or a protecting group;
- and
- L3 and L5 are each independently hydrogen or a protecting group, or L3 and L5 together are a protecting group;
- or a salt thereof.
A compound, wherein said compound is:
Dependencies are inferred from the claim text.