Synthesis method and intermediates useful in the preparation of pyrrolobenzodiazepines

1. A compound of formula I:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

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 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.

2. A compound according to claim 1 , wherein R 7 is OR A , where R A is unsubstituted C 1-4 saturated alkyl.

3. A compound according to claim 1 , wherein R S is CF 3 .

4. A compound according to claim 1 , wherein R C1 is methyl.

5. A compound according to claim 1 , wherein —Si—(R Si1 )(R Si2 )(R Si3 ) is TBDMS.

6. A method of synthesising a compound according to claim 1 from a compound of formula II:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

R 9 is selected from H, methyl and methoxy; and

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;

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 an inert atmosphere.

7. A compound of formula III:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

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;

(ii) an optionally substituted C 1-6 alkyl group; and

(iii) H.

8. A method of synthesising a compound according to claim 7 from a compound of formula I:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

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 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;

by:

(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.

9. A compound of formula IV:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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.

10. A compound according to claim 9 , wherein —Si—(R Si1 )(R Si2 )(R Si3 ) is TBDMS.

11. A compound according to claim 9 , wherein R C2 is methyl.

12. A method of synthesising a compound according to claim 9 from a compound of formula III:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

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;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-6 alkyl group; and

(iii) H;

by:

(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.

13. A compound of formula V:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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;

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:

14. A compound according to claim 13 , wherein R 10 is selected from one of:

DBD-Tmoc

Cbz (benzyl carbamate)

Voc (Vinyl carbamate)

1,1-dimethylpropynyl carbamate

Alloc (Allyl carbamate)

Moz (p- methoxybenzylcarbamate)

Ipaoc (1- isopropylallyl carbamate)

PNZ (p- nitrobenzylcarbamate)

Coc (Cinnamyl carbamate)

3,4-dimethoxy-6- nitrobenzyl carbamate

Noc (4- nitrocinnamyl carbamate)

p-bromobenzyl carbamate

Paloc (3-(3′- pyridyl)prop-2- enyl carbamate)

p-chlorobenzyl carbamate

N- hydroxypiperidinyl carbamate

2,4-dichlorobenzyl carbamate

1,1-dimethyl-2- bromoethyl carbamate

Bic (5- benzylisoxazolylmethyl)

1,1-dimethyl-2- chloroethyl carbamate

Diphenylmethyl carbamate

1,1-dimethy1-2- cyanoethyl carbamate

9-anthrylmethyl carbamate

Propynyl carbamate

S-benzyl carbamate

where the asterisk indicates the point of attachment to the N10 position.

15. A compound according to claim 13 , 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.

16. A method of synthesising a compound according to claim 13 from a compound of formula IV:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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 reaction of IV with triphosgene to obtain the isocyanate followed by reaction with R 10 —OH.

17. A compound of formula VI:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H; 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:

18. A method of synthesising a compound according to claim 17 from a compound of formula V:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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;

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:

by:

(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.

19. A method according to claim 18 , wherein the oxidation is carried out with Dess-Martin periodinane.

20. A compound of formula VII:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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:

and

R E is selected from the group consisting of: O—C 1-2 alkyl; O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are as defined above; O—CH 2 OCH 3 (OMOM), O—CH 2 OC 2 H 4 OCH 3 (OMEM), OC 5 H 10 (THP).

21. A compound according to claim 20 , wherein R E is O-TBS.

22. A method of synthesising a compound according to claim 20 from a compound of formula VI:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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:

by adding a protecting group to OH to yield R E .

23. A compound of formula VIII:

wherein:

R 7 is 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;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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:

and R E is selected from the group consisting of: O—C 1-2 alkyl; O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are as defined above; O—CH 2 OCH 3 (OMOM), O—CH 2 OC 2 H 4 OCH 3 (OMEM), OC 5 H 10 (THP).

24. A method of synthesising a compound according to claim 23 from a compound of formula VII:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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:

and

R E is selected from the group consisting of: O—C 1-2 alkyl; O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are as defined above; O—CH 2 OCH 3 (OMOM), O—CH 2 OC 2 H 4 OCH 3 (OMEM), OC 5 H 10 (THP);

by:

removing the protecting group in R 8 to yield OH.

25. A compound of formula IX:

wherein:

R 7 is 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;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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:

R E is selected from the group consisting of: O—C 1-2 alkyl; O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are as defined above; O—CH 2 OCH 3 (OMOM), O—CH 2 OC 2 H 4 OCH 3 (OMEM), OC 5 H 10 (THP);

n is from 1 to 12 and Hal is selected from I, Cl and Br.

26. A method of synthesising a compound according to claim 25 from a compound of formula VIII:

wherein:

R 7 is 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;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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:

and

R E is selected from the group consisting of: O—C 1-2 alkyl; O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are as defined above; O—CH 2 OCH 3 (OMOM), O—CH 2 OC 2 H 4 OCH 3 (OMEM), OC 5 H 10 (THP);

by reacting with a compound of formula X:

wherein Q is selected from I, Cl and Br.

27. A compound of formula XI:

wherein:

R 7 is 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;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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:

R E is selected from the group consisting of: O—C 1-2 alkyl; O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are as defined above; O—CH 2 OCH 3 (OMOM), O—CH 2 OC 2 H 4 OCH 3 (OMEM), OC 5 H 10 (THP);

where n is from 1 to 12;

and where R 2′ , R 7′ , R 9′ , R 10′ and R E′ are independently selected from the same groups as R 2 , R 7 , R 9 , R 10 and R E respectively.

28. A method of synthesising a compound according to claim 27 comprising coupling compounds of formulae VIII and IX:

wherein:

R 7 is 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;

R 8 is OProt O , where Prot O is a silicon-based oxygen protecting group orthogonal to R C ;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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:

and

R E is selected from the group consisting of: O—C 1-2 alkyl; O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are as defined above; O—CH 2 OCH 3 (OMOM), O—CH 2 OC 2 H 4 OCH 3 (OMEM), OC 5 H 10 (THP);

wherein:

R 7 is 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;

R 9 is selected from H, methyl and methoxy;

R 2 is selected from:

(i) an optionally substituted C 5-20 aryl group;

(ii) an optionally substituted C 1-5 alkyl group; and

(iii) H;

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:

R E is selected from the group consisting of: O—C 1-2 alkyl; O—Si—(R Si1 )(R Si2 )(R Si3 ), where R Si1 , R Si2 , R Si3 are as defined above; O—CH 2 OCH 3 (OMOM), O—CH 2 OC 2 H 4 OCH 3 (OMEM), OC 5 H 10 (THP);

n is from 1 to 12 and Hal is selected from I, Cl and Br.

29. The method according to claim 28 , wherein the reaction is carried out in refluxing acetone in the presence of K 2 CO 3 .