Some pyrrolobenzodiazepines (PBDs) have the ability to recognise and bond to specific sequences of DNA; the preferred sequence is PuGPu. The first PBD antitumour antibiotic, anthramycin, was discovered in 1965 (Leimgruber, et al., J. Am. Chem. Soc., 87, 5793-5795 (1965); Leimgruber, et al., J. Am. Chem. Soc., 87, 5791-5793 (1965)). Since then, a number of naturally occurring PBDs have been reported, and over 10 synthetic routes have been developed to a variety of analogues (Thurston, et al., Chem. Rev. 1994, 433-465 (1994)). Family members include abbeymycin (Hochlowski, et al., J. Antibiotics, 40, 145-148 (1987)), chicamycin (Konishi, et al., J. Antibiotics, 37, 200-206 (1984)), DC-81 (Japanese Patent 58-180 487; Thurston, et al., Chem. Brit., 26, 767-772 (1990); Bose, et al., Tetrahedron, 48, 751-758 (1992)), mazethramycin (Kuminoto, et al., J. Antibiotics, 33, 665-667 (1980)), neothramycins A and B (Takeuchi, et al., J. Antibiotics, 29, 93-96 (1976)), porothramycin (Tsunakawa, et al., J. Antibiotics, 41, 1366-1373 (1988)), prothracarcin (Shimizu, et al, J. Antibiotics, 29, 2492-2503 (1982); Langley and Thurston, J. Org. Chem., 52, 91-97 (1987)), sibanomicin (DC-102)(Hara, et al., J. Antibiotics, 41, 702-704 (1988); Itoh, et al., J. Antibiotics, 41, 1281-1284 (1988)), sibiromycin (Leber, et al., J. Am. Chem. Soc., 110, 2992-2993 (1988)) and tomamycin (Arima, et al., J. Antibiotics, 25, 437-444 (1972)). PBDs are of the general structure:

They differ in the number, type and position of substituents, in both their aromatic A rings and pyrrolo C rings, and in the degree of saturation of the C ring. In the B-ring there is either an imine (N═C), a carbinolamine (NH—CH(OH)), or a carbinolamine methyl ether (NH—CH(OMe)) at the N10-C11 position which is the electrophilic centre responsible for alkylating DNA. All of the known natural products have an (S)-configuration at the chiral C11a position which provides them with a right-handed twist when viewed from the C ring towards the A ring. This gives them the appropriate three-dimensional shape for isohelicity with the minor groove of B-form DNA, leading to a snug fit at the binding site (Kohn, In Antibiotics III. Springer-Verlag, New York, pp. 3-11 (1975); Hurley and Needham-VanDevanter, Acc. Chem. Res., 19, 230-237 (1986)). Their ability to form an adduct in the minor groove, enables them to interfere with DNA processing, hence their use as antitumour agents.
The present inventors have previously disclosed, in WO 2004/043963, cytotoxic compounds having an aryl group at the C2 position, for example:

The present inventors have also previously disclosed, in co-pending PCT application PCT/GB2005/000768 (published as WO 2005/085251), dimeric PBD compounds bearing C2 aryl substituents, such as:

The present inventors encountered some issues with the solubility of compounds such as ZC-207, which they resolved by the use of a different form of these compounds. This form is disclosed in pending PCT application PCT/GB2006/001456 (published as WO 2006/111759). It discloses compounds with the formula I:

or solvate thereof, wherein:
R2 is an optionally substituted C5-20 aryl group;
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;
R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo;
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, e.g. benzene or pyridine;
X is selected from O, S, or NH;
z is 2 or 3;
M is a monovalent pharmaceutically acceptable cation;
R2′, R6′, R7′, R9′, X′ and M′ are selected from the same groups as R2, R6, R7, R9, X and M respectively, or M and M′ may together represent a divalent pharmaceutically acceptable cation.
Pyrrolobenzodiazepines having an imine bond are known to convert to the di-carbinolamine form in water, and isolated pyrrolobenzodiazepines often exist as a mixture of the imine, mono-carbinolamine and di-carbinolamine forms. Furthermore, if the compound is isolated as a solid with a mixture of these three forms, the balance between them may change over time. Although this does not pose a problem for administration of the compound, it can provide difficulties in accurately assessing the amount of active substance in a given amount of powder. Compounds of the type disclosed in WO 2006/111759, at least to some extent, overcome this difficulty whilst remaining active, and are thus suited to formulation as pharmaceuticals.
Dimeric pyrrolobenzodiazepines offer advantages over monomeric pyrrolobenzodiazepines in that they possess the ability to cross-link DNA in the minor groove, which can lead to an increase in cytotoxicity.
A particularly advantageous compound in this class is disclosed in WO 2006/111759 as ZC-423, and shown below.

This compound is synthesised in WO 2006/111759 as Example 1.
However, the present inventors have found difficulties with this synthesis. In WO 2006/111759 the synthesis comprised a very large number of steps, which decreased the potential yield as well as adding to the experimental difficulty of synthesising the product.
There is a need therefore for an improved method of preparing ZC-423 that has fewer steps and provides an increased yield of the final product.