Method for producing c1-c15 fragments of epothilones and the derivatives thereof
This invention describes a process for the production of C 1 -C 15 -fragments of epothilones and derivatives thereof, in which a C1-C6-fragment is linked with a C7-C12-fragment to a C1-C12-fragment, and the latter then is reacted with a C13-15-fragment to form the C1-C15 initial epothilone product that is to be produced. The thus obtained C1-C15 initial epothilone products can be reacted according to known methods to form the actual active ingredients. In addition, the invention relates to the corresponding C1-C12-fragments.
1 . Process for the production of C 1 -C 15 -epothilone fragments of general formula I,
in which
R 1a , R 1b are the same or different and mean hydrogen, C 1 -C 10 -alkyl, aryl, C 7 -C 20 -aralkyl, or together mean a —(CH 2 ) m group with m=2, 3, 4 or 5,
R 2a , R 2b are the same or different and mean hydrogen, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkinyl, aryl, C 7 -C 20 -aralkyl or together mean a —(CH 2 ) n group with n=2, 3, 4 or 5,
R 3 means hydrogen, C 1 -C 10 -alkyl, aryl, C 7 -C 20 -aralkyl,
R 4a , R 4b are the same or different and mean hydrogen, C 1 -C 10 -alkyl, aryl, C 7 -C 20 -aralkyl or together mean a —(CH 2 ) p group with p=2, 3, 4 or 5,
R 5 means hydrogen, C 1 -C 10 -alkyl, aryl, C 7 -C 20 -aralkyl,
R 6 , R 7 each mean a hydrogen atom, together an additional bond or together an oxygen atom,
G means a group X═CR 8 —, a bicyclic or tricyclic aryl radical,
R 8 means hydrogen, halogen, C 1 -C 20 -alkyl, aryl, C 7 -C 20 -aralkyl, which all can be substituted,
X means an oxygen atom, two alkoxy groups OR 23 , a C 2 -C 10 -alkylene-α,ω-dioxy group, which can be straight-chain or branched, H/OR 9 or a grouping CR 10 R 11 ,
whereby
R 23 stands for a C 1 -C 20 -alkyl radical,
R 9 stands for hydrogen or a protective group PG X ,
R 10 , R 11 are the same or different and stand for hydrogen, a C 1 -C 20 -alkyl, aryl, or C 7 -C 20 -aralkyl radical, or R 10 and R 11 together with the methylene carbon atom together stand for a 5- to 7-membered carbocyclic ring,
R 13 means CH 2 OR 13a , CH 2 -Hal, CHO, CO 2 R 13b , or COHal,
R 14 means hydrogen, OR 14a , Hal, or OSO 2 R 14b ,
R 13a , R 14a mean hydrogen, SO 2 -alkyl, SO 2 -aryl, SO 2 -aralkyl or together a —(CH 2 ) o group or together a CR 15a R 15b group,
R 13b , R 14b mean hydrogen, C 1 -C 20 -alkyl, aryl, C 1 -C 20 -aralkyl,
R 15a , R 15b are the same or different and mean hydrogen, C 1 -C 10 -alkyl, aryl, C 7 -C 20 -aralkyl, or together a —(CH 2 ) q group,
o means 2 to 4,
q means 3 to 6,
R 20 means OPG 3 , NHR 29 , or N 3 ,
Z means an oxygen atom or H/OR 12 ,
whereby
R 12 is hydrogen or a protective group PG Z
including all stereoisomers as well as mixtures thereof, and
free hydroxyl groups in R 13 and R 14 can be etherified or esterified, free carbonyl groups in Z and R 13 can be ketalized, converted into an enol ether or reduced, and free acid groups in R 13 und R 14 can be converted into their salts with bases, characterized in that
a C1-C6 fragment (epothilone numbering system) of general formula A
in which
R 1a′ , R 1b′ , R 2a′ , R 2b′ , R 13′ and R 14′ have the meanings already mentioned for R 1a , R 1b , R 2a , R 2b , R 13 and R 4 , including all stereoisomers as well as mixtures thereof, and free hydroxyl groups in R 13 und R 14 can be etherified or esterified, free carbonyl groups in A und R 13 can be ketalized, converted into an enol ether or reduced, and free acid groups in A can be converted into their salts with bases,
is reacted with a C7-C12 fragment (epothilone numbering system) of general formula
in which
R 3a′ , R 4a′ , R 4b′ and R 5 have the meanings already mentioned for R 3a , R 4 and R 5 , and
V means an oxygen atom, two alkoxy groups OR 17 , a C 2 -C 10 -alkylene-α,ω-dioxy group, which can be straight-chain or branched, or H/OR 16 ,
W means an oxygen atom, two alkoxy groups OR 19 , a C 2 -C 10 -alkylene-α,ω-dioxy group, which can be straight-chain or branched, or H/OR 18 ,
R 16 , R 18 , independently of one another, mean hydrogen or a protective group PG 1 ,
R 17 , R 19 , independently of one another, mean C 1 -C20-alkyl,
to form a partial fragment of general formula AB
in which
R 1a′ , R 1b′ , R 2a′ , R 2b′ , R 3′ , R 4a′ , R 4b′ , R 5 , R 13′ , R 14′ , V and Z have the already-mentioned meanings, and
PG 14 represents a hydrogen atom or a protective group PG, and
this partial fragment of general formula AB is reacted with a C13-C15 fragment (epothilone numbering system) of general formula C
in which
G′ has the meaning already mentioned in general formula I for G, and
R 7′ means a hydrogen atom,
R 20′ means halogen, N 3 , NHR 29 , a hydroxy group, a protected hydroxy group O-PG 3 , a protected amino group NR 29 PG 3 , a C 1 -C 10 -alkylsulfonyloxy group, which optionally can be perfluorinated, a benzoyloxy group that is optionally substituted by C 1 -C 4 -alkyl, nitro, chlorine or bromine, an NR 29 SO 2 CH 3 group, an NR 29 C(═O)CH 3 group, or a CH 2 —C(═O)—CH 3 group,
R 21 means a hydroxy group, halogen, a protected hydroxy group OPG 3 , a phosphonium halide radical PPh 3 + Hal − (Ph=Phenyl; Hal=F, Cl, Br, I), a phosphonate radical P(O)(OQ) 2 (Q=C 1 -C 10 -alkyl or phenyl) or a phosphine oxide radical P(O)Ph 2 (Ph=Phenyl),
R 29 means hydrogen or C 1 -C 6 -alkyl,
to form a compound of general formula ABC (=compound of general formula I)
in which
R 1a′ , R 1b′ , R 2a′ , R 2b′ , R 3′ , R 4a′ , R 4b′ , R 5′ , R 6 , R 7 , R 13 , R 14 , G and Z have the already mentioned meanings, and
PG 14 represents a hydrogen atom or a protective group PG.
2 . Process according to claim 1 , wherein a compound of general formula I,
in which
R 1a , R 1b are the same and mean C 1 -C 6 -alkyl, or together mean a —(CH2) m group with m=2, 3or 4,
R 2a , R 2b are different and mean hydrogen, C 1 -C 6 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkinyl or C 7 -C 20 -aralkyl,
R 5 means hydrogen, C 1 -C 6 -alkyl,
R 8 means hydrogen, halogen, C 1 -C 6 -alkyl,
R 15a , R 15b are the same or different and mean hydrogen, C 1 -C 6 -alkyl, aryl, C 7 -C 20 -aralkyl, or together mean a —(CH 2 ) q group,
q means 3 to 6,
is produced.
3 . Process according to claim 1 , wherein a compound of general formula I,
in which
R 1a , R 1b are the same and mean C 1 -C 3 -alkyl, or together mean a —(CH 2 ) m group with m=2, 3 or 4,
R 2a means hydrogen,
R 2b means C 1 -C 5 -alkyl, C 2 -C 6 -alkenyl, or C 2 -C 6 -alkinyl,
R 5 means hydrogen, or C 1 -C 3 -alkyl,
R 6 , R 7 together mean an additional bond,
G means a group X═CR 8 —, or a bicyclic aryl radical,
R 8 means hydrogen, fluorine, chlorine, or C 1 -C 3 -alkyl,
X means oxygen or a group CR 10 R 11 ,
R 10 means hydrogen,
R 11 means aryl,
R 13 means CH 2 OR 13a or CO 2 R 13b ,
R 14 means OR 14a ,
R 13a , R 14a together mean a CR 15a R 15b group,
R 13b means hydrogen or C 1 -C 6 -alkyl,
R 15a , R 15b are the same and mean C 1 -C 3 -alkyl, or together mean a —(CH 2 ) q group, or
R 15a , R 15b are different and mean hydrogen or aryl,
q means 4 or 5,
Z means oxygen,
is produced.
4 . Process for the production of epothilone derivatives of general formula II
in which substituents R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 , G, OPG 2 and Z have the meanings that are indicated in general formula I, and
A-K means a group —O—C(═O), —OCH 2 —, —CH 2 C(═O)—, —NR 29 —C(═O)—, or —NR 29 —SO 2 —, wherein an initial epothilone product of general formula I that is obtained according to claim 1 is cyclized.
5 . Compounds of general formula AB
in which R 1a′ , R 1b′ , R 2a′ , R 2b′ , R 3′ , R 4a′ , R 4b′ , R 5 , R 13′ , R 14′ , V and Z have the already mentioned meanings, and PG 14 represents a hydrogen atom or a protective group PG.