US 2014/0275522 A1 · SYNTHESIS METHOD AND INTERMEDIATES USEFUL IN THE PREPARATION OF PYRROLOBENZODIAZEPINES

Abstract

A compound of formula I wherein: R7 is selected from: ORA, where RA is selected from C1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl; chloro; NH2; —CH2—O—C(═O)Me; R8 is OProto, where Proto is a silicon-based oxygen protecting group orthogonal to Rc; R9 is selected from H, methyl and methoxy; Rs is selected from CF3, (CF2)3CF3, CH3 and (formula 2) and Rc is selected from: (i) C(═O)—ORC1, where RC1 is a saturated C1-4 alkyl group; (ii) —CH2—O—C(═O)RC2, where RC2 is methyl or phenyl; (iii) CH2—O—Si—(RSi1)(RSi2)(RSi3), where RSi1, RSi2, RSi3 are independently selected from C1-6 a saturated alkyl group and a phenyl group; and (iv) C(—YRC3)(—YRC4) where each Y is independently O or S, and where RC3 and RC4 are independently a saturated C1-4 alkyl group, or together form a C2-3 alkylene.

Claims30

Dependent claims

-42. (canceled)

A compound of formula III:

wherein:
R7 is selected from:
ORA, where RA is selected from C1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl;
chloro;
NH2;
—CH2—O—C(═O)Me;
R8 is OProtO, where ProtO is a silicon-based oxygen protecting group orthogonal to RC;
R9 is selected from H, methyl and methoxy;
RC is selected from:
(i) —C(═O)—ORC1, where RC1 is a saturated C1-4 alkyl group;
(ii) —CH2—O—C(═O)RC2, where RC2 is methyl or phenyl;
(iii) —CH2—O—Si—(RSi1)(RSi2)(RSi3), where RSi1, RSi2, RSi3 are independently selected from C1-6 a saturated alkyl group and a phenyl group;
and
(iv) —C(—YRC3)(—YRC4) where each Y is independently O or S, and where RC3 and RC4 are independently a saturated C1-4 alkyl group, or together form a C2-3 alkylene;
and
R2 is selected from:
(i) an optionally substituted C5-20 aryl group;
(ii) an optionally substituted C1-6 alkyl group;
and
(iii) H.

17 more elements

A compound of formula IV:

wherein:
R7 is selected from:
ORA, where RA is selected from C1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl;
chloro;
NH2;
—CH2—O—C(═O)Me;
R8 is OProtO, where ProtO is a silicon-based oxygen protecting group orthogonal to RC;
R9 is selected from H, methyl and methoxy;
R2 is selected from:
(i) an optionally substituted C5-20 aryl group;
(ii) an optionally substituted C1-5 alkyl group;
and
(iii) H;
RD is selected from:
(ii) —CH2—O—C(═O)RC2, where RC2 is methyl or phenyl;
(iii) —CH2—O—Si—(RSi1)(RSi2)(RSi3), where RSi1, RSi2, RSi3 are independently selected from C1-6 saturated alkyl group and a phenyl group;
and
(iv) —C(—YRC3)(—YRC4) where each Y is independently O or S, and where RC3 and RC4 are independently a saturated C1-4 alkyl group, or together form a C2-3 alkylene.

15 more elements

A compound of formula V:

wherein:
R7 is selected from:
ORA, where RA is selected from C1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl;
chloro;
NH2;
—CH2—O—C(═O)Me;
R8 is OProtO, where ProtO is a silicon-based oxygen protecting group orthogonal to RC;
R9 is selected from H, methyl and methoxy;
R2 is selected from:
(i) an optionally substituted C5-20 aryl group;
(ii) an optionally substituted C1-5 alkyl group;
and
(iii) H;
RD is selected from:
(ii) —CH2—O—C(═O)RC2, where RC2 is methyl or phenyl;
(iii) —CH2—O—Si—(RSi1)(RSi2)(RSi3), where RSi1, RSi3 are independently selected from C1-6 saturated alkyl group and a phenyl group;
and
(iv) —C(—YRC3)(—YRC4) where each Y is independently O or S, and where RC3 and RC4 are independently a saturated C1-4 alkyl group, or together form a C2-3 alkylene;
R10 is a carbamate-based nitrogen protecting group, which is palladium-labile and/or labile under the conditions used to add the group:
or contains a moiety which is palladium-labile and/or is labile under the conditions used to add the group:

17 more elements

A compound of formula VI:

wherein:
R7 is selected from:
ORA, where RA is selected from C1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl;
chloro;
NH2;
—CH2—O—C(═O)Me;
R8 is OProtO, where ProtO is a silicon-based oxygen protecting group orthogonal to RC;
R9 is selected from H, methyl and methoxy;
R2 is selected from:
(i) an optionally substituted C5-20 aryl group;
(ii) an optionally substituted C1-5 alkyl group;
and
(iii) H;
and
R10 is a carbamate-based nitrogen protecting group, which is palladium-labile and/or labile under the conditions used to add the group:
or contains a moiety which is palladium-labile and/or is labile under the conditions used to add the group:

13 more elements

A compound of formula XI:

wherein:
R7 is selected from:
ORA, where RA is selected from C1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl;
chloro;
NH2;
—CH2—O—C(═O)Me;
R9 is selected from H, methyl and methoxy;
R2 is selected from:
(i) an optionally substituted C5-20 aryl group;
(ii) an optionally substituted C1-5 alkyl group;
and
(iii) H;
R10 is a carbamate-based nitrogen protecting group, which is palladium-labile and/or labile under the conditions used to add the group:
or contains a moiety which is palladium-labile and/or is labile under the conditions used to add the group:
RE is selected from the group consisting of:
O—C1-2 alkyl;
O—Si—(RSi1)(RSi2)(RSi3), where RSi1, RSi2, RSi3 are as defined above;
O—CH2OCH3 (OMOM), O—CH2OC2H4OCH3 (OMEM), OC5H10 (THP);
and where R2′, R7′, R9′, R10′ and RE′ are independently selected from the same groups as R2, R7, R9, R10 and RE respectively.

16 more elements

Dependencies are inferred from the claim text.

Synthesis method and intermediates useful in the preparation of pyrrolobenzodiazepines

Life of this patent

Synthesis method and intermediates useful in the preparation of pyrrolobenzodiazepines

Life of this patent

Abstract

Claims30