Pyrrolobenzodiazepines as key intermediates in the synthesis of dimeric cytotoxic pyrrolobenzodiazepines

A compound of formula IIIa or IIIb:

• and salts and thereof, wherein:
• the dotted lines indicates the optional presence of a double bond between C1 and C2 or C2 and C3;
• R2 and R3 are independently selected from —H, ═O, ═CH2, —CN, —R, OR, halo, ═CH—R, O—SO2—R, CO2R and COR;
• R6, R9, R12 and R13 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;
• where R and R′ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups;
• R10 is a carbamate-based nitrogen protecting group and R15 is either O—R11, wherein R11 is an oxygen protecting group, or OH, or R10 and R15 together form a double bond between N10 and C11;
• and
• where R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NH, and/or aromatic rings, and each X is independently selected from O, S, or NH;
• and
• R2′, R3′, R6′, R9′, R10′, R12′, R13′ and R15′ are all independently selected from the same lists as previously defined for R2, R3, R6, R9, R10, R12, R13 and R15 respectively.

A method of synthesising a compound of formula Ia or Ib:

• from a compound of formula IIa or IIb respectively:
• wherein:
• the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3;
• R2 and R3 are independently selected from —H, ═O, ═CH2, —CN, —R, OR, halo, ═CH—R, O—SO2—R, CO2R and COR;
• R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;
• where R and R′ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups;
• RA is selected from H, R, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;
• R10 is a carbamate-based nitrogen protecting group;
• R11 is an oxygen protecting group;
• and
• R14 is an oxygen protecting group orthogonal to R11.

A method of synthesising a compound of formula IIIa or IIIb:

• or a solvate thereof, from a compound of formula Ia or Ib respectively:
• wherein:
• the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3;
• R2 and R3 are independently selected from —H, ═O, ═CH2, —CN, —R, OR, halo, ═CH—R, O—SO2—R, CO2R and COR;
• R6, R9, R12 and R13 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;
• where R and R′ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups;
• RA is selected from H, R, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;
• R10 is a carbamate-based nitrogen protecting group and R15 is either O—R11, wherein R11 is an oxygen protecting group, or OH, or R10 and R15 together form a double bond between N10 and C11;
• and
• where R″ is a C3-12 alkylene group, and each X is independently selected from O, S, or NH;
• and
• R2′, R3′, R6′, R9′, R10′, R12′, R13′ and R15′ are all independently selected from the same lists as previously defined for R2, R3, R6, R9, R10, R12, R13 and R15 respectively.