Intermediates useful for the synthesis of pyrrolobenzodiazepines
View Patent ↗A compound of formula (I): which is substantially free of any of the corresponding compound of formula (IB): methods of making such compounds, and the further transformation of such compounds.
1. A compound of formula I:
wherein:
R 7 and R 8 are independently selected from: OR A , where R A is selected from C 1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl; chloro; NH 2 ; —CH 2 —O—C(═O)Me;
or R 7 and R 8 together form a group —O—(CH 2 ) m —O—, where m is 1 or 2;
or the compound is a dimer with each monomer independently being of formula (I), where the R 7 groups or R 8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C 3-12 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 NH 2 , and each X is independently selected from O, S, or NH;
R 9 is selected from H, methyl and methoxy;
R s is selected from CF 3 , (CF 2 ) 3 CF 3 , CH 3 and
and
R C is selected:
(i) —C(═O)—OR c1 , where R C1 is a saturated C 1-4 alkyl group;
(ii) —CH 2 —O—C(═O)R c2 , where R C2 is methyl or phenyl;
(iii) —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 )where R Si1 , R Si2 , R Si3 are independently selected from C 1-6 a saturated alkyl group and a phenyl group; and
(iv) —C(—YR C3 )(—YR C4 ) where each Y is independently O or S, and where R C3 and R C4 are independently a saturated C 1-4 alkyl group, or together form a C 2-3 alkylene,
which is substantially free of any of the corresponding compound of formula IB:
2. A compound according to claim 1 , wherein R 7 and R 8 are independently OR A , where R A is selected from C 1-4 saturated alkyl, optionally substituted by phenyl, pyridyl and furanyl.
3. A compound according to claim 1 , wherein R A is unsubstituted C 1-4 saturated alkyl.
4. A compound according to claim 3 , wherein R A is methyl.
5. A compound according to claim 1 which is a dimer, where each X is O.
6. A compound according to claim 1 which is a dimer, where R″ is a C 3 , C 5 or C 7 saturated alkylene group.
7. A compound according to claim 1 , wherein R S is CF 3 .
8. A compound according to claim 1 , wherein R C1 is methyl.
9. A compound according to claim 1 , wherein —Si—(R Si1 )(R Si2 )(R Si3 ) is TBDMS.
10. A method of synthesising a compound of formula I:
as defined in claim 1 , 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.
11. The method according to claim 10 , wherein the reaction is carried out at a temperature of −40° C. or lower.
12. A compound of formula III:
wherein:
R 7 and R 8 are independently selected from: OR A ,where R A is selected from C 1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl; chloro; NH 2 ; —CH 2 —O—C(═O)Me;
or R 7 and R 8 together form a group —O—(CH 2 ) m —O—, where m is 1 or 2;
or the compound is a dimer with each monomer independently being of formula (III), where the R 7 groups or R 8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C 3-12 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 NH 2 , and each X is independently selected from O, S, or NH;
R 9 is selected from H, methyl and methoxy;
R c is selected from:
(i) —C(═O)—OR c1 , where R c1 is a saturated C 1-4 alkyl group;
(ii) —CH 2 —O—C(═O)R C2 , where R C2 is methyl or phenyl;
(iii) —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 , are independently selected from C 1-6 a saturated alkyl group and a phenyl group; and
(iv) —C(—YR C3 )(—YR C4 ) where each Y is independently O or S, and where R C3 and R C4 are independently a saturated C 1-4 alkyl group or together form a C 2-3 alkylene; and
R 2 is selected from:
(i) an optionally substituted C 5-20 aryl group wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-ox -alkylene and N—C 1-4 alkyl piperazinyl; and
(ii) an optionally substituted C 2-5 alkenyl group or C 2-5 alkynyl group, wherein the optional substituents are chosen from:
(i) optionally substituted C 5-20 aryl groups wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl;
(ii) —CN;
(iii) —C(═O)—NR N1 R N2 , where R N1 and R N2 are C 1-7 alkyl groups;
(iv) —C(═O )—OR O , where R O is a C 1-7 alkyl group;
(v)—OR O ;
(vi) —Sn(R SN ) 3 where R SN is a C 1-7 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:
13. A method of synthesising a compound of formula III:
wherein:
R 7 and R 8 are independently selected from: OR A , where R A is selected from C 1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl; chloro; NH 2 ; —CH 2 —O—C(═O)Me;
or R 7 and R 8 together form a group —O—(CH 2 ) m —O—, where m is 1 or 2;
or the compound is a dimer with each monomer independently being of formula (III), where the R 7 groups or R 8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers where R″ is a C 3-12 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 NH 2 , and each X is independently selected from O, S, or NH; R 9 is selected from H, methyl and methoxy;
R C is selected from:
(i) —C(═O)—OR C1 , where R C1 is a saturated C 1-4 alkyl group;
(ii) —CH 2 —O—C(═O)R C2 , where R C2 is methyl or phenyl;
(iii) —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 ), where Si1 , R Si2 , R Si3 are independently selected from C 1-6 a saturated alkyl group and a phenyl group; and
(iv) —C(—YR C3 )(—YR C4 ) where each Y is independently O or S, and where R C3 and R C4 are independently a saturated C 1-4 alkyl group, or together form a C 2-3 alkylene; and
R 2 is selected from:
(i) an optionall substituted C 5-20 aryl group wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl; and
(ii) an optionally substituted C 2-5 alkenyl group or C 2-5 alkynyl group, wherein the optional substituents are chosen from:
(i) optionally substituted C 5-20 aryl groups wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl;
(ii) —CN;
(iii) —C(═O)—NR N1 R N2 where R N1 and R N2 are C 1-7 alkly groups;
(iv) —C(═O)—OR O is a C 1-7 alkyl group;
(v) —OR O ;
(vi) —Sn(R SN ) 3 where R SN is a C 1-7 alkyl group;
from a compound of formula I:
wherein:
R S is selected from CF 3 , (CF 2 ) 3 CF 3 , CH 3 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.
14. A compound of formula IV:
wherein R 7 and R 8 are independently selected from: OR A , where R A is selected from C 1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl; chloro; NH 2 ; —CH 2 —O—C(═O)Me;
or R 7 and R 8 together form a group —O—(CH 2 ) m —O—, where m is 1 or 2;
or the compound is a dimer with each monomer independently being of formula (IV), where the R 7 groups or R 8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C 3-12 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 NH 2 , and each X is independently selected from O, S, or NH;
R 9 is selected from H, methyl and methoxy;
R 2 is selected from:
(i) an optionally substituted C 5-20 aryl group wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy -alkylene and N—C 1-4 alkyl piperazinyl;
and
(ii) an optionally substituted C 2-5 alkenyl group or C 2-5 alkynyl group, wherein the optional substituents are chosen from:
(i) optionally substituted C 5-20 aryl groups wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl;
(ii) —CN;
(iii) —C(═O)—NR N1 R N2 where R N1 and R N2 are C 1-7 alkly groups;
(iv) —C(═O)—OR O is a C 1-7 alkyl group;
(v) —OR O ;
(vi) —Sn(R SN ) 3 where R SN is a C 1-7 alkyl group; and
R D is selected from:
(ii) —CH 2 —O—C(═O)R C2 , where R C2 is methyl or phenyl;
(iii) —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are independently selected from C 1-6 saturated alkyl group and a phenyl group; and
(iv) —C(—YR C3 )(—YR C4 ) where each Y is independently O or S, and where R C3 and R C4 are independently a saturated C 1-4 alkyl group, or together form a C 2-3 alkylene,
which is substantially free of any of the corresponding compound of formula IVB:
15. A compound according to claim 14 , wherein —Si—(R Si1 )(R Si2 )(R Si3 ) is TBDMS.
16. A compound according to claim 14 , wherein R C2 is methyl.
17. A method of synthesising a compound of formula IV:
wherein R 7 and R 8 are independently selected from: OR A , where R A is selected from C 1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl; chloro; NH 2 ; —CH 2 —O—C(═O)Me;
or R 7 and R 8 together form a group —O—(CH 2 ) m —O—, where m is 1 or 2;
or the compound is a dimer with each monomer independently being of formula (IV), where the R 7 groups or R 8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C 3-12 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 NH 2 , and each X is independently selected from O, S, or NH;
R 9 is selected from H, methyl and methoxy;
R c is selected from:
(i) an optionally substituted C 5-20 aryl group wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-ox -alkylene and N—C 1-4 alkyl piperazinyl; and
(ii) an optionally substituted C 2-5 alkenyl group or C 2-5 alkynyl group, wherein the optional substituents are chosen from:
(i) optionally substituted C 5-20 aryl groups wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl;
(ii) —CN;
(iii) —C(═O)—NR N1 R N2 , where R N1 and R N2 are C 1-7 alkyl groups;
(iv) —C(═O )—OR O , where R O is a C 1-7 alkyl group;
(v) —OR O ;
—Sn(R SN ) 3 where R SN is a C 1-7 alkyl group; and
R D is selected from:
(ii) —CH 2 —O—C(═O)R C2 , where R C2 is methyl or phenyl;
(iii) —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are independently selected from C 1-6 saturated alkyl group and a phenyl group; and
(iv) —C(—YR C3 )(—YR C4 ) where each Y is independently O or S, and where R C3 and R C4 are independently a saturated C 1-4 alkyl group, or together form a C 2-3 alkylene, from a compound of formula III:
wherein:
R C is selected from:
(i) —C(═O)—OR C1 , where R C1 is a saturated C 1-4 alkyl group;
(ii) —CH 2 —O—C(═O)R C2 , where R C2 is methyl or phenyl;
(iii) —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 ), where Si1 , R Si2 , R Si3 are independently selected from C 1-6 a saturated alkyl group and a phenyl group; and
(iv) —C(—YR C3 )(—YR C4 ) where each Y is independently O or S, and where R C3 and R C4 are independently a saturated C 1-4 alkyl group, or together form a C 2-3 alkylene; and
by one of the following:
(i) if R C is —C(═O)—OR C1 , conversion of —C(═O)—OR C1 to —CH 2 —O—C(═O)R C2 or —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 ), followed by:
(ii) if R C is —CH 2 —O—C(═O)R C2 , reduction of the nitro group by zinc in acetic acid or if R C is —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 ), reduction of the nitro group using zinc in 5% formic acid in ethanol;
(iii) if R C is —C(—YR C3 )(—YR C4 ), 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.
18. A compound of formula V:
wherein R 7 and R 8 are independently selected from: OR A , where R A is selected from C 1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl; chloro; NH 2; —CH 2 —O—C(═O)Me;
or R 7 and R 8 together form a group —O—(CH 2 ) m —O—, where m is 1 or 2;
or the compound is a dimer with each monomer independently being of formula (V), where the R 7 groups or R 8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C 3-12 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 NH 2 , and each X is independently selected from O, S, or NH;
R 9 is selected from H, methyl and methoxy;
R 2 is selected from:
(i) an optionally substituted C 5-20 aryl group wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-ox -alkylene and N—C 1-4 alkyl piperazinyl; and
(ii) an optionally substituted C 2-5 alkenyl group or C 2-5 alkynyl group, wherein the optional substituents are chosen from:
(i) optionally substituted C 5-20 aryl groups wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl;
(ii) —CN;
(iii) —C(═O)—NR N1 R N2 , where R N1 and R N2 are C 1-7 alkyl groups;
(iv) —C(═O )—OR O , where R O is a C 1-7 alkyl group;
(v) —OR O ;
(vi) —Sn(R SN ) 3 where R SN is a C 1-7 alkyl group; and
R D is selected from:
(ii) —CH 2 —O—C(═O)R C2 , where R C2 is methyl or phenyl;
(iii) —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are independently selected from C 1-6 saturated alkyl group and a phenyl group; and
(iv) —C(—YR C3 )(—YR C4 ) where each Y is independently O or S, and where R C3 and R C4 are independently a saturated C 1-4 alkyl group, or together form a C 2-3 alkylene; and
R 10 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:
19. A compound according to claim 18 , wherein R 10 is selected from one of:
where the asterisk indicates the point of attachment to the N10 position.
20. A compound according to claim 18 , wherein R 10 is of the formula:
where the asterisk indicates the point of attachment to the N10 position, G 1 is a functional group to form a connection to a cell binding agent, L 1 is a cleavable linker, L 2 is a covalent bond or together with —OC(═O)— forms a self-immolative linker.
21. A method of synthesising a compound of formula V:
wherein R 7 and R 8 are independently selected from: OR A , where R A is selected from C 1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl; chloro; NH 2 ; —CH 2 —O—C(═O)Me;
or R 7 and R 8 together form a group —O—(CH 2 ) m —O—, where m is 1 or 2;
or the compound is a dimer with each monomer independently being of formula (V), where the R 7 groups or R 8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers where R″ is a C 3-12 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 NH 2 , and each X is independently selected from O, S, or NH;
R 9 is selected from H, methyl and methoxy;
R 2 is selected from:
(i) an optionally substituted C 5-20 aryl group wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl; and
(ii) an optionally substituted C 2-5 alkenyl group or C 2-5 alkynyl group, wherein the optional substituents are chosen from:
(i) optionally substituted C 5-20 aryl groups wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl;
(ii) —CN;
(iii) —C(═O)—NR N1 R N2 , where R N1 and R N2 are C 1-7 alkyl groups;
(iv) —C(═O)—OR O , where R O is a C 1-7 alkyl group;
(v) —OR O ;
(vi) —Sn(R SN ) 3 where R SN is a C 1-7 alkyl group; and
R D is selected from:
(ii) —CH 2 —O—C(═O)R C2 , where R C2 is methyl or phenyl;
(iii) —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are independently selected from C 1-6 saturated alkyl group and a phenyl group; and
(iv) —C(—YR C3 )(—YR C4 ) where each Y is independently O or S, and where R C3 and R C4 are independently a saturated C 1-4 alkyl group, or together form a C 2-3 alkylene; and
R 10 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 R 10 —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.
22. A compound of formula VI:
wherein R 7 and R 8 are independently selected from: OR A , where R A is selected from C 1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl; chloro; NH 2 ; —CH 2 —O—C(═O)Me;
or R 7 and R 8 together form a group —O—(CH 2 ) m —O—, where m is 1 or 2;
or the compound is a dimer with each monomer independently being of formula (VI), where the R 7 groups or R 8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers where R″ is a C 3-12 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 NH 2 , and each X is independently selected from O, S, or NH;
R 9 is selected from H, methyl and methoxy;
R 2 is selected from:
(i) an optionally substituted C 5-20 aryl group wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl; and
(ii) an optionally substituted C 2-5 alkenyl group or C 2-5 alkynyl group, wherein the optional substituents are chosen from:
(i) optionally substituted C 5-20 aryl groups wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl;
(ii) —CN;
(iii) —C(═O)—NR N1 R N2 , where R N1 and R N2 are C 1-7 alkyl groups;
(iv) —C(═O)—OR O , where R O is a C 1-7 alkyl group;
(v) —OR O ;
(vi) —Sn(R SN ) 3 where R SN is a C 1-7 alkyl group; and
R 10 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:
23. A method of synthesising a compound of formula VI:
wherein R 7 and R 8 are independently selected from: OR A , where R A is selected from C 1-4 saturated alkyl, optionally substituted by phenyl, which may bear a chloro substituent, pyridyl and furanyl; chloro; NH 2 ; —CH 2 —O—C(═O)Me;
or R 7 and R 8 together form a group —O—(CH 2 ) m —O—, where m is 1 or 2;
or the compound is a dimer with each monomer independently being of formula (VI), where the R 7 groups or R 8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers where R″ is a C 3-12 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 NH 2 , and each X is independently selected from O, S, or NH;
R 9 is selected from H, methyl and methoxy;
R 2 is selected from:
(i) an optionally substituted C 5-20 aryl group wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl; and
(ii) an optionally substituted C 2-5 alkenyl group or C 2-5 alkynyl group, wherein the optional substituents are chosen from:
(i) optionally substituted C 5-20 aryl groups wherein the optional substituents are chosen from halo, C 1-7 alkoxy, di-C 1-4 alkylamino-C 1-7 alkoxy, C 1-7 alkyl, bis-oxy-alkylene and N—C 1-4 alkyl piperazinyl;
(ii) —CN;
(iii) —C(═O)—NR N1 R N2 , where R N1 and R N2 are C 1-7 alkyl groups;
(iv) —C(═O)—OR O , where R O is a C 1-7 alkyl group;
(v) —OR O ;
(vi) —Sn(R SN ) 3 where R SN is a C 1-7 alkyl group; and
R 10 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 R D is selected from:
(ii) —CH 2 —O—C(═O)R C2 , where R C2 is methyl or phenyl;
(iii) —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are independently selected from C 1-6 saturated alkyl group and a phenyl group; and
(iv) —C(—YR C3 )(—YR C4 ) where each Y is independently O or S, and where R C3 and R C4 are independently a saturated C 1-4 alkyl group, or together form a C 2-3 alkylene by one of the following:
(a) (i) where R D is —CH 2 —O—C(═O)Me, removal of the acetate protecting group, with potassium carbonate in aqueous methanol, or with lithium triethylborohydride;
(ii) where R D is —CH 2 —O—Si—(R Si1 )(R Si2 )(R Si3 ), 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 R D is —C(—YR C3 )(—YR C4 ), 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.
24. A method according to claim 23 , wherein the oxidation is carried out with Dess-Martin periodinane.