US 2014/0179917 A1 · PREPARATION OF MAYTANSINOID ESTERS

A method for preparing a maytansinoid C-3 ester comprising contacting a maytansinoid with a carboxylic acid in the presence of a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid catalyst, a base, and a coupling reagent.

A method of preparing a compound of Formula I or a salt thereof:

comprising contacting a compound of Formula I-A:
with a carboxylic acid of the formula R—COOH in the presence of a coupling reagent, a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid catalyst and a base to form the compound of Formula I, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(═O)R5;
R1 is selected from the group consisting of hydrogen, - and —OR17;
R2 is hydrogen or C1-C6 alkyl;
R3 is methyl, —CH2OH, or —CH2OR17;
R4 is —OH, —OR17 or —SH;
R5 is C1-C6 alkyl or benzyl;
R17 is a hydroxy protecting group;
R is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein the alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclic is optionally substituted with one to three R10, or is
L is selected from optionally substituted C1-C20 alkylene, C3-C8 cycloalkylene, and optionally substituted C1-C20 alkylene wherein one or more of the —CH2— group is independently replaced with C3-C8 cycloalkylene, —O—, —S—, —C(O)—, —NR8—, —C(═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4-SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C1-4 alkyl, —CONR11R11, and —NR11Pr;
R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
R8 is hydrogen or C1-6 alkyl;
each R10 is independently selected from the group consisting of —NR11Pr, —NR11COCH2Br, —COOR12, —CONR11R11, —NR11COR13,
—S—S—R13, —Si(R13)3, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic;
each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two OXO;
Pr is an amino protecting group;
R12 is C1-C6 alkyl, or benzyl;
and
each R13 is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclic.

20 more elements

A method of preparing a compound of Formula II, or a salt thereof:

comprising contacting a compound of Formula II-A:
with a carboxylic acid of the formula R—COOH in the presence of a coupling reagent, a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid catalyst and a base to form the compound of Formula II, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(═O)R5;
R1 is selected from the group consisting of hydrogen, —OH, and —OR17;
R2 is hydrogen or C1-C6 alkyl;
R3 is methyl, —CH2OH, or CH2OR17;
R4 is —OH, —OR17 or —SH;
R5 is C1-C6 alkyl or benzyl;
R17 is a hydroxy protecting group;
R is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein the alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclic is optionally substituted with one to three R10, or is
L is selected from optionally substituted C1-C20 alkylene, C3-C8 cycloalkylene, and optionally substituted C1-C20 alkylene wherein one or more of the —CH2— group is independently replaced with C3-C8 cycloalkylene, —O—, —S—, —C(O)—, —NR8—, —C(═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
wherein substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4-SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-8 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C1-4 alkyl, —CONR11R11, and —NR11Pr;
R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
R8 is hydrogen or C1-8 alkyl;
each R10 is independently selected from the group consisting of —NR11Pr, —NR11COCH2Br, —COOR12, —CONR11R11, —NR11COR13,
—S—S—R13, —Si(R13)3, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic;
each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
Pr is an amino protecting group;
R12 is C1-C6 alkyl, or benzyl;
and
each R13 is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclic.

20 more elements

A method of preparing a compound of Formula III, or a salt thereof:

comprising contacting a compound of Formula III-A:
with a carboxylic acid of Formula III-B III-B
in the presence of a coupling reagent, a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid catalyst and a base to form the compound of Formula III, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(═O)R5;
R1 is selected from the group consisting of hydrogen, —OH, and —OR17;
R2 is hydrogen or C1-C6 alkyl;
R3 is methyl, —CH2OH, or CH2OR17;
R4 is —OH, —OR17 or —SH;
R5 is C1-C6 alkyl or benzyl;
R17 is a hydroxy protecting group;
R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
R8 is hydrogen or C1-6 alkyl;
and
L is selected from optionally substituted C1-C20 alkylene, C3-C8 cycloalkylene, and optionally substituted C1-C20alkylene wherein one or more of the —CH2— group is independently replaced with C3-C8 cycloalkylene, —O—, —S—, —C(O)—, —NR8—, —C(═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
wherein substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4-SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C1-4 alkyl, —CONR11R11, and —NR11Pr.

14 more elements

A composition comprising a compound of Formula I-A:

a carboxylic acid of the formula R—COOH, and a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(═O)R5;
R1 is selected from the group consisting of hydrogen, —OH, and —OR17;
R2 is hydrogen or C1-C6 alkyl;
R3 is methyl, —CH2OH, or CH2OR17;
R4 is —OH, —OR17 or —SH;
R5 is C1-C6 alkyl or benzyl;
R17 is a hydroxy protecting group;
R is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein the alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclic is optionally substituted with one to three R10, or is
L is selected from optionally substituted C1-C20 alkylene, C3-C8 cycloalkylene, and optionally substituted C1-C20alkylene wherein one or more of the —CH2— group is independently replaced with C3-C8cycloalkylene, —O—, —S—, —C(O)—, —NR8—, —C(═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4-SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C1-4 alkyl, —CONR11R11, and —NR11Pr;
R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
R8 is hydrogen or C1-6 alkyl;
each R10 is independently selected from the group consisting of —NR11Pr, —NR11COCH2Br, —COOR12, —CONR11R11, —NR11COR13,
—S—S—R13, —Si(R13)3, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic;
each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two OXO;
Pr is an amino protecting group;
R12 is C1-C6 alkyl, or benzyl;
and
each R13 is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclic.

19 more elements

A composition comprising a compound of Formula II-A:

a carboxylic acid of the formula R—COOH, and a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(═O)R5;
R1 is selected from the group consisting of hydrogen, —OH, and —OR17;
R2 is hydrogen or C1-C6 alkyl;
R3 is methyl, —CH2OH, or CH2OR17;
R4 is —OH, —OR17 or —SH;
R5 is C1-C6 alkyl or benzyl;
R17 is a hydroxy protecting group;
R is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein the alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclic is optionally substituted with one to three R10, or is
L is selected from optionally substituted C1-C20 alkylene, C3-C8 cycloalkylene, and optionally substituted C1-C20 alkylene wherein one or more of the —CH2— group is independently replaced with C3-C8 cycloalkylene, —O—, —S—, —C(O)—, —NR8—, —C(═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
wherein substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4-SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C1-4 alkyl, —CONR11R11, and —NR11Pr;
R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
R8 is hydrogen or C1-6 alkyl;
each R10 is independently selected from the group consisting of —NR11Pr, —NR11COCH2Br, —COOR12, —CONR11R11, —NR11COR13,
—S—S—R13, —Si(R13)3, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic;
each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
Pr is an amino protecting group;
R12 is C1-C6 alkyl, or benzyl;
and
each R13 is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclic.

19 more elements

A method of preparing a compound of Formula XII:

or a salt thereof,
comprising contacting a compound of Formula X:
with a carboxylic acid of Formula III-H
in the presence of a coupling reagent or directly with its active ester to form the compound of Formula XII, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(═O)R5;
R1 is selected from the group consisting of hydrogen, —OH, and —OR17;
R2 is hydrogen or C1-C6 alkyl;
R3 is methyl, —CH2OH, or —CH2OR17;
R4 is —OH, —OR17 or —SH;
R5 is C1-C6 alkyl or benzyl;
R17 is a hydroxy protecting group;
R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
R8 is hydrogen or C1-6 alkyl;
and
L is selected from optionally substituted C1-C20 alkylene, C3-C8 cycloalkylene, and optionally substituted C1-C20 alkylene wherein one or more of the —CH2-group is independently replaced with C3-C8 cycloalkylene, —O—, —S—, —NR10—, —C(═O)NR10—, —NR10C(═O)—, —SO2NR10—, or —NR10SO2—;
substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4-SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C1-4 alkyl, —CONR11R11, and —NR11Pr;
FG is independently selected from the group consisting of —NR11Pr, —NR11COCH2Br, —COOR12, —CONR11R11, —NR11COR13,
—S—S—R13, —Si(R13)3, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic;
each R10 or R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
Pr is an amino protecting group;
R12 is C1-C6 alkyl, or benzyl;
and
each R13 is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclic.

22 more elements

A method of preparing a compound of Formula IIIa, or a salt thereof:

comprising contacting a compound of Formula X:
with a carboxylic acid of Formula III-C
in the presence of a coupling reagent or directly with its active ester to form the compound of Formula III, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(═O)R5;
R1 is selected from the group consisting of hydrogen, —OH, and —OR17;
R2 is hydrogen or C1-C6 alkyl;
R3 is methyl, —CH2OH, or —CH2OR17;
R4 is —OH, —OR17 or —SH;
R5 is C1-C6 alkyl or benzyl;
R17 is a hydroxy protecting group;
R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
R8 is hydrogen or C1-6 alkyl;
and
L is selected from optionally substituted C1-C20 alkylene, C3-C8 cycloalkylene, and optionally substituted C1-C20 alkylene wherein one or more of the —CH2— group is independently replaced with C3-C8 cycloalkylene, —O—, —S—, —C(O)—, —NR8—, —C(═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
wherein substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4-SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, 5-C1-4 alkyl, —CONR11R11, and —NR11Pr.

14 more elements

A method of preparing a compound of Formula XV, or a salt thereof:

comprising contacting a compound of Formula X:
with a sulfonyl chloride of Formula XV-A
in the presence of a base to form the compound of Formula XV, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(═O)R5;
R1 is selected from the group consisting of hydrogen, —OH, and —OR17;
R2 is hydrogen or C1-C6 alkyl;
R3 is methyl, —CH2OH, or —CH2OR17;
R4 is —OH, —OR17 or —SH;
R5 is C1-C6 alkyl or benzyl;
R17 is a hydroxy protecting group;
R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
R8 is hydrogen or C1-6 alkyl;
and
L is selected from optionally substituted C1-C20 alkylene, C3-C8 cycloalkylene, and optionally substituted C1-C20 alkylene wherein one or more of the —CH2— group is independently replaced with C3-C8 cycloalkylene, —O—, —S—, —C(O)—, —NR8—, —C(═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
wherein substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4-SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C1-4 alkyl, —CONR11R11, and —NR11Pr.

14 more elements

Preparation of maytansinoid esters

Life of this patent

Abstract

Claims78

Preparation of maytansinoid esters

Life of this patent

Abstract

Claims78