US 2018/0002342 A1 · MACROCYCLIZATION REACTIONS AND INTERMEDIATES USEFUL IN THE SYNTHESIS OF ANALOGS OF HALICHONDRIN B

Abstract

The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Horner-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate. The invention also provides compounds useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for preparing the same.

Claims93

Dependent claims

A method of preparing an intermediate in the synthesis of eribulin, said method comprising performing a macrocyclization reaction on a non-macrocyclic intermediate, said macrocyclization reaction producing said intermediate in the synthesis of eribulin by forming C.15-C.16, C.2-C.3, C.3-C.4, C.19-C.20, C.0-C.1, or C.26-C.27 bond in the structure of eribulin.

A method of preparing:

said method comprising:
(A) producing a compound of formula (IB) from a compound of formula (IA), the compound of formula (IA) having the following structure:
wherein
R1 is H or —CH2X1CH2CH═CH2, wherein X1 is O, —C(R9)2—, or NP5, and wherein each R9 is independently H or —COOR10, P5 is an N-protecting group, and R10 is C1-6 alkyl;
(a1) R2 is H or a hydroxyl protecting group, R3 is C1-6 alkyl ether, and R4 is H;
(a2) R2 is H or a hydroxyl protecting group, and R3 and R4 combine to form a double bond;
or
(a3) R2 and R3 combine to form a bond, and R4 is H;
(b1) R5 is H or a hydroxyl protecting group, and R6 and R7 combine to form a double bond;
or
(b2) R5 and R6 combine to form a bond, and R7 is H;
(c1) R8 is H, and P4 is H or a hydroxyl protecting group;
or
(c2) R8 and P4 combine to form a double bond;
each P3 is independently H or a hydroxyl protecting group;
and
X is O, and
each of P1 and P2 is independently H or a hydroxyl protecting group,
or
P1 and P2, together with the atoms to which each is attached, combine to form a cyclic protected diol;
or
X is N, and
P1 is H or a hydroxyl protecting group, and X and P2 combine to form optionally masked amino;
or
P1 and P2, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl;
the compound of formula (IB) having the following structure:
(B) producing a compound of formula (IC) from the compound of formula (IB), the compound of formula (IC) having the following structure:
(C) producing a compound of formula (ID) from the compound of formula (IC), the compound of formula (ID) having the following structure:
wherein
each P3 is independently H or a hydroxyl protecting group, and X2 is oxo;
or both P3 groups and X2, together with the atoms to which each is attached, combine to form ketal;
and
(D) producing eribulin or eribulin mesylate from the compound of formula (ID).

30 more elements

A method of preparing:

said method comprising:
(A) producing a compound of formula (IIIB) from the compound of formula (IIIA), the compound of formula (IIIA) having the following structure:
wherein
(i) R1 is H or a hydroxyl protecting group, and R2 and R3 combine to form a double bond;
or
(ii) R1 and R2 combine to form a bond, and R3 is H;
X3 is oxo, or X3 combines with the carbon atom to which it is attached to form a ketal, a thioketal, or —(CH(OP5))—, wherein P5 is H or a hydroxyl protecting group;
each P3 is independently H or a hydroxyl protecting group, and X2 is oxo;
or both P3 groups and X2, together with the atoms to which each is attached, combine to form ketal;
P4 is H or a hydroxyl protecting group;
and
X is O, and
each of P1 and P2 is independently H or a hydroxyl protecting group,
or
P1 and P2, together with the atoms to which each is attached, combine to form a cyclic protected diol;
or
X is N, and
P1 is H or a hydroxyl protecting group, and X and P2 combine to form optionally masked amino;
or
P1 and P2, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl;
the compound of formula (IIIB) having the following structure:
(B) producing a compound of formula (ID) from the compound of formula (IIIB), the compound of formula (ID) having the following structure:
and
(C) producing eribulin or eribulin mesylate from the compound of formula (ID).

21 more elements

A method of preparing

said method comprising:
(A) producing a compound of formula (IVB) from a compound of formula (IVA), the compound of formula (IVA) having the following structure:
wherein
Y is iodide, bromide, or trifluoromethanesulfonate;
a designates R stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide;
or a designates S stereogenic center, and Z is OR1, wherein R1 is a hydroxyl protecting group;
(i) R2 is H or a hydroxyl protecting group, and R3 and R4 combine to form a double bond;
or
(ii) R2 and R3 combine to form a bond, and R4 is H;
each P3 is independently H or a hydroxyl protecting group, and X2 is oxo;
or both P3 groups and X2, together with the atoms to which each is attached, combine to form ketal;
and
X is O, and
each of P1 and P2 is independently H or a hydroxyl protecting group,
or
P1 and P2, together with the atoms to which each is attached, combine to form a cyclic protected diol;
or
X is N, and
P1 is H or a hydroxyl protecting group, and X and P2 combine to form optionally masked amino;
or
P1 and P2, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl;
the compound of formula (IVB) having the following structure:
wherein
a designates R stereogenic center, b designates S stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide;
or
a designates S stereogenic center, b designates R stereogenic center, and Z is OR1, wherein R1 is a hydroxyl protecting group;
(B) producing a compound of formula (ID) from the compound of formula (IVB), the compound of formula (ID) having the following structure:
and
(C) producing eribulin or eribulin mesylate from the compound of formula (ID).

26 more elements

A method of preparing:

said method comprising:
(A) producing a compound of formula (VB) from a compound of formula (VA):
wherein
Y is SO2R1 or COOR1, wherein, when Y is SO2R1, R1 is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COOR1, R1 is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
each P3 is independently H or a hydroxyl protecting group, and X2 is oxo, or both P3 groups and X2, together with the atoms to which each is attached, combine to form ketal;
R2 is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted aryl;
and
X is O, and
each of P1 and P2 is independently a hydroxyl protecting group,
or
P1 and P2, together with the atoms to which is each is attached, combine to form a cyclic protected diol;
or
X is N, and
P1 is H or a hydroxyl protecting group, and X and P2 combine to form optionally masked amino;
or
P1 and P2, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl;
the compound of formula (VB) having the following structure:
wherein
(i) R3 is H, R4 is ether, and R5 is H;
(ii) R5 is H, and R3 and R4, together with the bond connecting the atoms to which each is attached, combine to form a double bond;
or
(iii) R3 is H, and R4 and R5 combine to form a bond;
(B) producing a compound of formula (ID) from the compound of formula (VB), the compound of formula (ID) having the following structure:
and
(C) producing eribulin or eribulin mesylate from the compound of formula (ID).

22 more elements

A method of preparing:

said method comprising:
(A) producing a compound of formula (VIB) from a compound of formula (VIA), the compound of formula (VIA) having the following structure:
wherein
Y is iodide, bromide, or trifluoromethanesulfonate;
(a1) R3 is H or a hydroxyl protecting group, R4 and R5 combine to form a double bond, each P3 is independently H or a hydroxyl protecting group, and X2, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR6))—, wherein R6 is H or a hydroxyl protecting group;
or
(a2) R3 and R4 combine to form a bond, R5 is H, and
each P3 is independently H or a hydroxyl protecting group, and X2, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR6))—;
or
both P3 groups and X2, together with the atoms to which each is attached, combine to form ketal;
(b1) Z is chloride, bromide, or iodide, and R1 and R2 combine to form a bond;
or
(b2) Z and R2 combine to form a double bond, and R1 is H or a hydroxyl protecting group;
and
X is O, and
each of P1 and P2 is independently H or a hydroxyl protecting group,
or
P1 and P2, together with the atoms to which each is attached, combine to form a cyclic protected diol;
or
X is N, and
P1 is H or a hydroxyl protecting group, and X and P2 combine to form optionally masked amino;
or
P1 and P2, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl;
and
the compound of formula (VIB) having the following structure:
wherein P4 is H or a hydroxyl protecting group;
(B) producing a compound of formula (VIC) from the compound of formula (VIB), the compound of formula (VIC) having the following structure:
(C) producing a compound of formula (ID) from the compound of formula (VIC), the compound of formula (ID) having the following structure:
and
(D) producing eribulin or eribulin mesylate from the compound of formula (ID).

27 more elements

A method of preparing an intermediate in the synthesis of eribulin, said method comprising:

(A) cleaving the double bond in a compound of formula (VIIIA) to afford a compound of formula (VIIIB), the compound of formula (VIIIA) having the structure:
wherein
X1 is oxo, or X1, together with the carbon atom to which it is attached, forms a ketal or —(CH(OP3))—, wherein P3 is H or a hydroxyl protecting group;
R1 is H or —CH2OP4;
each of P1, P2, and P4 is independently a hydroxyl protecting group, or
P1 and P4, together with the atoms to which each is attached, combine to form a cyclic protected diol;
and
the compound of formula (VIIIB) having the structure:
(B) reacting the compound of formula (VIIIB) with a compound of formula (VIIIB-a) to afford a compound of formula (VIIIC):
wherein R2 is H or —CH2CH2OP5, and P5 is a hydroxyl protecting group;
and the compound of formula (VIIIB-a) has the following structure:
(C) reacting the compound of formula (VIIIC) with a dehydrating agent to afford a compound of formula (VIIID):
(D) reacting the compound of formula (VIIID) with a dihydroxylating agent to afford a compound of formula (VIIIE):
(E) preparing a compound of formula (VIIIF) through a reaction sequence comprising reacting the compound of formula (VIIIE) with N-bromosuccinimide to afford a first intermediate, reacting said first intermediate with an acylating agent to afford a second intermediate, and (a), when R2 is —CH2CH2OP5, contacting said second intermediate with a reducing agent, or (b), when R2 is H, allylating said second intermediate compound of formula (VIIIF):
wherein Z is an ester or —OP7, wherein P7 is H or a hydroxyl protecting group, and R3 is —CH2CH2OP5 or —CH2CH═CH2;
(F) reacting the compound of formula (VIIIF) with a 1,4-reducing agent to afford a compound of formula (VIIIG):
(G) forming a compound of formula (VIIIH) through a reaction sequence comprising reacting the compound of formula (VIIIG) with a Brønsted acid and Y—H, wherein Y is optionally substituted C1-6 alkyl, the compound of formula (VIIIH) having the following structure:
wherein Y is optionally substituted C1-6 alkyl ether;
R2 is —CH2CH2OP5;
X2 is oxo, or X2, together with the carbon to which it is attached, forms a ketal or —(CH(OP6))—, wherein P6 is a hydroxyl protecting group.

17 more elements

Dependencies are inferred from the claim text.

Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin b

Life of this patent

Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin b

Life of this patent

Abstract

Claims93