Synthesis of protected pyrrolobenzodiazepines

1. A method of synthesis of a compound of formula (I):

comprising the steps of:

(a) reacting a compound of formula (II) with a compound of formula (III) to yield a compound of formula (IV):

(b) converting the compound of formula (IV) to a compound of formula (I):

wherein

the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3;

R 2 and R 3 are independently selected from —H, —OH, ═O, ═CH 2 , —CN, —R, OR, ═CH—R, O—SO 2 —R, CO 2 R and COR;

R 6 , R 7 and R 9 are independently H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;

R 8 is either selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me 3 Sn and halo or the compound is a dimer with each monomer being the same of different and being of the relevant formula, where the R 8 groups of each monomer form together a bridge having the formula —X—R″—X—, where R″ is a C 3−12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, and each X is independently selected from O, S and NH;

R 10 is such that R 10 —OC(═O)— forms a nitrogen protecting group;

R 11 is either H or R;

R 12 is an optionally substituted C 1−4 alkyl group;

P and Q are such that —CPQ is a masked aldehyde group;

wherein R and R′ are independently selected from optionally substituted C 1−20 alkyl, C 3−20 heterocyclyl, and C 5−20 aryl;

wherein T is O or S, and each R ac , is independently selected from C 1−10 alkyl or together can be a C 1−3 alkylene group.

2. A method according to claim 1 , wherein the compound of formula (II) is synthesized by:

3. A method of synthesis of a compound of formula (I):

comprising the steps of:

(a) reacting a compound of formula (V) with a compound of formula (III) to yield a compound of formula (VI):

(b) converting the compound of formula (VI) to the compound of formula (I):

wherein

the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3;

R 2 and R 3 are independently selected from —H, —OH, ═O, ═CH 2 , —CN, —R, OR, ═CH—R, O—SO 2 —R, CO 2 R and COR;

R 6 , R 7 and R 9 are independently H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;

R 8 is either selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo or the compound is a dimer with each monomer being the same of different and being of the relevant formula, where the R 8 groups of each monomer form together a bridge having the formula —X—R″—X—, where R″ is a C 3−12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, and each X is independently selected from O, S and NH;

R 10 is such that R 10 —OC(═O)— forms a nitrogen protecting group;

R 11 is either H or R;

R 12 is an optionally substituted C 1−4 alkyl group;

P and Q are such that —CPQ is a masked aldehyde group;

wherein R and R′ are independently selected from optionally substituted C 1−20 a C 3−20 heterocyclyl, and C 5−20 aryl.

4. A method according to claim 3 , wherein the compound of formula (IV) is synthesized by:

5. A compound of formula (IV):

wherein:

R 6 and R 7 are independently H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;

R 9 is H;

R 8 is either selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me 3 Sn and halo or the compound is a dimer with each monomer being the same of different and being of the relevant formula, where the R 8 groups of each monomer form together a bridge having the formula —X—R″—X—, where R″ is a C 3−12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, and each X is independently selected from O, S and NH;

R 10 is such that R 10 —OC(═O)— forms a nitrogen protecting group; and

R 12 is an optionally substituted C 1−4 alkyl group,

wherein R and R′ are independently selected from optionally substituted C 1−20 alkyl, C 3−20 heterocyclyl, and C 5−20 aryl.

6. A method according to claim 1 or claim 3 , wherein R 10 is an optionally substituted C 1−30 alkyl group, C 3−30 heterocylyl group or a C 5−30 aryl group or a divalent version of one of these groups linked to a solid support.

7. A compound according to claim 5 , wherein R 10 is an optionally substituted C 1−30 alkyl group, C 3−30 heterocylyl group or a C 5−30 aryl group or a divalent version of one of these groups linked to a solid support.