Process for making duocarmycin prodrugs
The present invention relates to a process comprising converting a compound of formula (I) into a compound of formula (II) by reaction with an organolithium reagent, which compound can be further converted into duocarmycin analogs consisting of a DNA-alkylating and a DNA-binding part, and still further into corresponding antibody-drug conjugates.
1. A process comprising converting a compound of formula (I)
into a compound of formula (II)
by reaction with a monometal organolithium reagent in a suitable solvent, wherein P and P′ are independently protective groups,
R 1 is CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , CF 3 , OCF 3 , Cl or F,
R 2 , R 3 , and R 4 are independently H or C 1-6 alkyl or
R 1 and R 2 taken together form a 5- or 6-membered (hetero)cycloalkyl group and
X is halogen.
2. The process according to claim 1 , wherein R 1 is CH 3 , CH 2 CH 3 , OCH 3 or OCH 2 CH 3 , R 2 , R 3 , and R 4 are independently H or C 1-6 alkyl or R 1 and R 2 taken together form a 5-membered (hetero)cycloalkyl group.
3. The process according to claim 1 , wherein the monometal organolithium reagent is selected from the group consisting of n-butyl lithium, tert-butyl lithium and methyl lithium.
4. The process according to claim 1 , wherein the halogen is bromine or iodine.
5. The process according to claim 1 , wherein a strong base is added.
6. The process according to claim 1 , further comprising converting the compound of formula (II) into a compound of formula (III)
by either a one-step or two-step reaction with a chlorinating reagent,
wherein R 1 , R 2 , R 3 , R 4 , P and P′ are as defined in claim 1 .
7. The process according to claim 6 , wherein the chlorinating reagent is selected from the group consisting of LiCl, KCl, NaCl, NH 4 Cl, HCl, AlCl 3 in concentrated HCl, PPh 3 /CCl 4 , PPh 3 /NCS, SOCl 2 and PCl 3 /PCl 5 .
8. The process according to claim 7 , wherein the chlorinating reagent is LiCl or PPh 3 /CCl 4 .
9. The process according to claim 6 , further comprising converting the compound of formula (III) into a compound of formula (IV)
by
a) removal of the P protective group from the compound of formula (III) and
b) reaction of the unprotected compound of formula (III) with a compound of formula (V)
in the presence of a coupling reagent followed by
c) elimination of the P′ protective group,
wherein R 1 , R 2 , R 3 , R 4 , P and P′ are as defined in claim 6 ,
P″ is independently a protective group and
X 1 , X 2 , are X 3 are independently C or N.
10. The process according to claim 9 , wherein the coupling reagent is selected from the group consisting of BOP, DCC, DIC, EDC, HATU, TBTU and T3P.
11. The process according to claim 10 , wherein the coupling reagent is EDC.
12. The process according to claim 1 , wherein the compound of formula (II) is
13. The process according to claim 9 , wherein the compound of formula (IV) is
14. The process according to claim 9 , further comprising isolating the compound of formula (IV).