Intermediates useful for the synthesis of pyrrolobenzodiazepines

A compound of formula III:

• wherein:
• R7 and R8 are independently 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;
• or R7 and R8 together form a group —O—(CH2)m—O—, where m is 1 or 2;
• or the compound is a dimer with each monomer independently being of formula (III), where the R7 groups or R8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C3-12 saturated alkylene group, which group may be interrupted by O, S, NH, NMe, phenylene or pyridylene, where the phenylene and pyridylene groups are optionally substituted by NH2, and each X is independently selected from O, S, or NH;
• 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 wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7 alkoxy, C1-7 alkyl, bis-ox -alkylene and N—C1-4 alkyl piperazinyl;
• and
• (ii) an optionally substituted C2-5 alkenyl group or C2-5 alkynyl group, wherein the optional substituents are chosen from:
• (i) optionally substituted C5-20 aryl groups wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7 alkoxy, C1-7 alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• (ii) —CN;
• (iii) —C(═O)—NRN1RN2, where RN1 and RN2 are C1-7 alkyl groups;
• (iv) —C(═O )—ORO, where RO is a C1-7 alkyl group;
• (v)—ORO;
• (vi) —Sn(RSN)3 where RSN is a C1-7 alkyl group;
• and
• wherein at least one of the unsaturated bonds is conjugated to the double bond present between C2 and C3;
• which is substantially free of any of the corresponding compound of formula IIIB:

A method of synthesising a compound of formula III:

• wherein:
• R7 and R8 are independently 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;
• or R7 and R8 together form a group —O—(CH2)m—O—, where m is 1 or 2;
• or the compound is a dimer with each monomer independently being of formula (III), where the R7 groups or R8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers where R″ is a C3-12 saturated alkylene group, which group may be interrupted by O, S, NH, NMe, phenylene or pyridylene, where the phenylene and pyridylene groups are optionally substituted by NH2, and each X is independently selected from O, S, or NH;
• 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 Si1, 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 optionall substituted C5-20 aryl group wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7 alkoxy, C1-7 alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• and
• (ii) an optionally substituted C2-5 alkenyl group or C2-5 alkynyl group, wherein the optional substituents are chosen from:
• (i) optionally substituted C5-20 aryl groups wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7 alkoxy, C1-7 alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• (ii) —CN;
• (iii) —C(═O)—NRN1RN2 where RN1 and RN2 are C1-7 alkly groups;
• (iv) —C(═O)—ORO is a C1-7 alkyl group;
• (v) —ORO;
• (vi) —Sn(RSN)3 where RSN is a C1-7 alkyl group;
• from a compound of formula I:
• wherein:
• RS is selected from CF3, (CF2)3CF3, CH3 and
• and
• comprising one of the following:
• (i) a Suzuki coupling between a compound of formula I and an appropriate aryl boron derivative;
• (ii) a Heck coupling with an appropriate alkene, acrylamide or acrylate;
• (iii) a Stille coupling with an appropriate organotin reagent;
• (iv) a Sonagishira coupling with an appropriate alkyne;
• or
• (v) a hydride transfer using a triethylsilane, wherein the compound of formula I is synthesised from a compound of formula II:
• comprising treating II with the appropriate anhydride and anhydrous 2,6-lutidine or anhydrous 2,6-tBu-pyridine at a temperature of −35° C. or lower in a dry organic solvent under a inert atmosphere.

A compound of formula IV:

• wherein R7 and R8 are independently 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;
• or R7 and R8 together form a group —O—(CH2)m—O—, where m is 1 or 2;
• or the compound is a dimer with each monomer independently being of formula (IV), where the R7 groups or R8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C3-12 saturated alkylene group, which group may be interrupted by O, S, NH, NMe, phenylene or pyridylene, where the phenylene and pyridylene groups are optionally substituted by NH2, and each X is independently selected from O, S, or NH;
• R9 is selected from H, methyl and methoxy;
• R2 is selected from:
• (i) an optionally substituted C5-20 aryl group wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7 alkoxy, C1-7 alkyl, bis-oxy -alkylene and N—C1-4 alkyl piperazinyl;
• and
• (ii) an optionally substituted C2-5 alkenyl group or C2-5 alkynyl group, wherein the optional substituents are chosen from:
• (i) optionally substituted C5-20 aryl groups wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7 alkoxy, C1-7 alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• (ii) —CN;
• (iii) —C(═O)—NRN1RN2 where RN1 and RN2 are C1-7 alkly groups;
• (iv) —C(═O)—ORO is a C1-7 alkyl group;
• (v) —ORO;
• (vi) —Sn(RSN)3 where RSN is a C1-7 alkyl group;
• and
• 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,
• which is substantially free of any of the corresponding compound of formula IVB:

A method of synthesising a compound of formula IV:

• wherein R7 and R8 are independently 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;
• or R7 and R8 together form a group —O—(CH2)m—O—, where m is 1 or 2;
• or the compound is a dimer with each monomer independently being of formula (IV), where the R7 groups or R8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C3-12 saturated alkylene group, which group may be interrupted by O, S, NH, NMe, phenylene or pyridylene, where the phenylene and pyridylene groups are optionally substituted by NH2, and each X is independently selected from O, S, or NH;
• R9 is selected from H, methyl and methoxy;
• Rc is selected from:
• (i) an optionally substituted C5-20 aryl group wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7 alkoxy, C1-7 alkyl, bis-ox -alkylene and N—C1-4 alkyl piperazinyl;
• and
• (ii) an optionally substituted C2-5 alkenyl group or C2-5 alkynyl group, wherein the optional substituents are chosen from:
• (i) optionally substituted C5-20 aryl groups wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7 alkoxy, C1-7 alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• (ii) —CN;
• (iii) —C(═O)—NRN1RN2, where RN1 and RN2 are C1-7 alkyl groups;
• (iv) —C(═O )—ORO, where RO is a C1-7 alkyl group;
• (v) —ORO;
• —Sn(RSN)3 where RSN is a C1-7 alkyl group;
• and
• 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, from a compound of formula III:
• wherein:
• 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 Si1, 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
• by one of the following:
• (i) if RC is —C(═O)—ORC1, conversion of —C(═O)—ORC1 to —CH2—O—C(═O)RC2 or —CH2—O—Si—(RSi1)(RSi2)(RSi3), followed by:
• (ii) if RC is —CH2—O—C(═O)RC2, reduction of the nitro group by zinc in acetic acid or if RC is —CH2—O—Si—(RSi1)(RSi2)(RSi3), reduction of the nitro group using zinc in 5% formic acid in ethanol;
• (iii) if RC is —C(—YRC3)(—YRC4), reduction of the nitro group using Cd/Pb couple, sodium dithionite or tin II chloride, wherein the compound of formula III is synthesised from a compound of formula II:
• comprising treating II with the appropriate anhydride and anhydrous 2,6-lutidine or anhydrous 2,6-tBu-pyridine at a temperature of −35° C. or lower in a dry organic solvent under a inert atmosphere.

A compound of formula V:

• wherein R7 and R8 are independently 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;
• or R7 and R8 together form a group —O—(CH2)m—O—, where m is 1 or 2;
• or the compound is a dimer with each monomer independently being of formula (V), where the R7 groups or R8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C3-12 saturated alkylene group, which group may be interrupted by O, S, NH, NMe, phenylene or pyridylene, where the phenylene and pyridylene groups are optionally substituted by NH2, and each X is independently selected from O, S, or NH;
• R9 is selected from H, methyl and methoxy;
• R2 is selected from:
• (i) an optionally substituted C5-20 aryl group wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7 alkoxy, C1-7 alkyl, bis-ox -alkylene and N—C1-4 alkyl piperazinyl;
• and
• (ii) an optionally substituted C2-5 alkenyl group or C2-5 alkynyl group, wherein the optional substituents are chosen from:
• (i) optionally substituted C5-20 aryl groups wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7 alkoxy, C1-7 alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• (ii) —CN;
• (iii) —C(═O)—NRN1RN2, where RN1 and RN2 are C1-7 alkyl groups;
• (iv) —C(═O )—ORO, where RO is a C1-7 alkyl group;
• (v) —ORO;
• (vi) —Sn(RSN)3 where RSN is a C1-7 alkyl group;
• and
• 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;
• 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:
• which is substantially free of any of the corresponding compound of formula VB:

A method of synthesising a compound of formula V:

• wherein R7 and R8 are independently 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;
• or R7 and R8 together form a group —O—(CH2)m—O—, where m is 1 or 2;
• or the compound is a dimer with each monomer independently being of formula (V), where the R7 groups or R8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers where R″ is a C3-12 saturated alkylene group, which group may be interrupted by O, S, NH, NMe, phenylene or pyridylene, where the phenylene and pyridylene groups are optionally substituted by NH2, and each X is independently selected from O, S, or NH;
• R9 is selected from H, methyl and methoxy;
• R2 is selected from:
• (i) an optionally substituted C5-20 aryl group wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4alkylamino-C1-7alkoxy, C1-7alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• and
• (ii) an optionally substituted C2-5 alkenyl group or C2-5 alkynyl group, wherein the optional substituents are chosen from:
• (i) optionally substituted C5-20 aryl groups wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7alkoxy, C1-7alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• (ii) —CN;
• (iii) —C(═O)—NRN1RN2, where RN1 and RN2 are C1-7 alkyl groups;
• (iv) —C(═O)—ORO, where RO is a C1-7 alkyl group;
• (v) —ORO;
• (vi) —Sn(RSN)3 where RSN is a C1-7 alkyl group;
• and
• 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;
• 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:
• from a compound of formula IV:
• by reaction of IV with triphosgene to obtain the isocyanate followed by reaction with R10—OH, wherein the compound of formula IV is synthesised from a compound of formula II:
• including the method comprising treating II with the appropriate anhydride and anhydrous 2,6-lutidine or anhydrous 2,6-tBu-pyridine at a temperature of −35° C. or lower in a dry organic solvent under a inert atmosphere.

A compound of formula VI:

• wherein R7 and R8 are independently 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;
• or R7 and R8 together form a group —O—(CH2)m—O—, where m is 1 or 2;
• or the compound is a dimer with each monomer independently being of formula (VI), where the R7 groups or R8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers where R″ is a C3-12 saturated alk lene rou which group may be interrupted by O, S, NH, NMe, phenylene or pyridylene, where the phenylene and pyridylene groups are optionally substituted by NH2, and each X is independently selected from O, S, or NH;
• R9 is selected from H, methyl and methoxy;
• R2 is selected from:
• (i) an optionally substituted C5-20 aryl group wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4alkylamino-C1-7alkoxy, C1-7alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• and
• (ii) an optionally substituted C2-5 alkenyl group or C2-5 alkynyl group, wherein the optional substituents are chosen from:
• (i) optionally substituted C5-20 aryl groups wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7alkoxy, C1-7alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• (ii) —CN;
• (iii) —C(═O)—NRN1RN2, where RN1 and RN2 are C1-7 alkyl groups;
• (iv) —C(═O)—ORO, where RO is a C1-7 alkyl group;
• (v) —ORO;
• (vi) —Sn(RSN)3 where RSN is a C1-7 alkyl group;
• 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:
• which is substantially free of any of the corresponding compound of formula VIB:

A method of synthesising a compound of formula VI:

• wherein R7 and R8 are independently 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;
• or R7 and R8 together form a group —O—(CH2)m—O—, where m is 1 or 2;
• or the compound is a dimer with each monomer independently being of formula (VI), where the R7 groups or R8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers where R″ is a C3-12 saturated alkylene group, which group may be interrupted by O, S, NH, NMe, phenylene or pyridylene, where the phenylene and pyridylene groups are optionally substituted by NH2, and each X is independently selected from O, S, or NH;
• R9 is selected from H, methyl and methoxy;
• R2 is selected from:
• (i) an optionally substituted C5-20 aryl group wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4alkylamino-C1-7alkoxy, C1-7alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• and
• (ii) an optionally substituted C2-5 alkenyl group or C2-5 alkynyl group, wherein the optional substituents are chosen from:
• (i) optionally substituted C5-20 aryl groups wherein the optional substituents are chosen from halo, C1-7 alkoxy, di-C1-4 alkylamino-C1-7alkoxy, C1-7alkyl, bis-oxy-alkylene and N—C1-4 alkyl piperazinyl;
• (ii) —CN;
• (iii) —C(═O)—NRN1RN2, where RN1 and RN2 are C1-7 alkyl groups;
• (iv) —C(═O)—ORO, where RO is a C1-7 alkyl group;
• (v) —ORO;
• (vi) —Sn(RSN)3 where RSN is a C1-7 alkyl group;
• 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:
• from a compound of formula V:
• wherein 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 by one of the following:
• (a) (i) where RD is —CH2—O—C(═O)Me, removal of the acetate protecting group, with potassium carbonate in aqueous methanol, or with lithium triethylborohydride;
• (ii) where RD is —CH2—O—Si—(RSi1)(RSi2)(RSi3), removal of the silyl ether protecting group using:
• TBAF in THF;
• acetic acid in aqueous THF;
• CsF in DMF;
• or HF in pyridine;
• and
• (b) oxidation of the product of step (a);
• or
• (c) where RD is —C(—YRC3)(—YRC4), removal of the acetal or thioacetal protecting groups, respectively with acid or reaction with Hg (II) salts, wherein the compound of formula V is synthesised from a compound of formula II:
• including the method comprising treating II with the appropriate anhydride and anhydrous 2,6-lutidine or anhydrous 2,6-tBu-pyridine at a temperature of −35° C. or lower in a dry organic solvent under a inert atmosphere.