Process for preparing inhibitors of nucleoside metabolism
View Patent ↗A process of preparing a compound of the formula (I) wherein B is chosen from OH, NH 2 , NHR, H or halogen; D is chosen from OH, NH 2 , NHR, H halogen or SCH 3 ; R is an optionally substituted alkyl, aralkyl or aryl group; and Z is selected from OH, hydrogen, halogen, hydroxy, SQ or OQ, Q is an optionally substituted alkyl, aralkyl or aryl group; or a tautomer thereof; or a pharmaceutically acceptable salt thereof; or an ester thereof; or a prodrug thereof, which comprises reacting a compound of the formula (II) with an anion produced by abstraction of the bromine or iodine atom from a compound of formula (XIX), to form a compound of formula (XX) The compound of formula (LXX) is N- and O-deprotected to obtain the compound of formula (I).
1. A compound of formula (XX):
wherein R 9 is a hydrogen atom, an alkoxycarbonyl or aralkyloxycarbonyl group, Z′ is a hydrogen or halogen atom, a hydroxy group, a group of formula SQ or OQ, or a trialkylsilyloxy, alkyldiarylsilyloxy or optionally substituted triarylmethoxy group and Q is an optionally substituted alkyl, aralkyl or aryl group, and R 6 is an N-protecting group, B′ and D′ are independently selected from H, OR 7 and N(R 8 ) 2 , and R 7 and R 8 are O- and N-protecting groups respectively.
2. A compound as claimed in claim 1 wherein R 9 is a hydrogen atom or a tert-butoxycarbonyl group, Z′ is a hydroxy group, a tert-butyldimethylsilyloxy or methylthio group, and R 6 is a benzyloxymethyl, allyl, tert-butyldimethylsilyl, 2-(trimethylsilylethoxy)methyl or benzyl group, B′ is a methoxy, tert-butoxy or benzyloxy group and D′ is a hydrogen or fluorine atom, a dibenzylamino group or a bis(4-methoxybenzyl) amino group.
3. A compound as defined in claim 1 , selected from the following compounds:
(1S)-1-C-(5-N-Benzyloxymethyl-4-methoxypyrrolo[3,2-d]pyrimidin-7-yl)-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol;
(1S)-5-O-tert-Butyldimethylsilyl-1,4-dideoxy-1,4-imino-2,3-isopropylidene-1-C-{14-methoxy-5-N-(2-trimethylsilyl)ethoxymethylpyrrolo[3,2-d]pyrimidin-7-yl}-D-ribitol;
(1S)-1-C-(5-N-Allyl-4-methoxypyrrolo[3,2-d]pyrimidin-7-yl)-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol;
(1S)-1-C-(4-Benzyloxy-5-N-tert-butyldimethylsilyl-2-fluoropyrrolo[3,2-d]pyrimidin-7-yl)-5-O-tert-butyldimethylsilyl-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol;
(1S)-1-C-(4-Benzyloxy-5-N-benzyloxymethyl-2-fluoropyrrolo[3,2-d]pyrimidin-7-yl)-5-O-tert-butyldimethylsilyl-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol;
(1S)-1-C-{4-Benzyloxy-5-N-(2-trimethylsilylethoxy)methylpyrrolo[3,2-d]pyrimidin-7-yl)-N-tert-butoxycarbonyl-5-O-tert-butyldimethylsilyl-1,4-dideoxy-1,4-imino-2,3-)O-isopropylidene-D-ribitol;
(1S)-1-C-(4-Benzyloxy-5-N-benzyloxymethylpyrrolo[3,2-d]pyrimidin-7-yl)-N-tert-butoxycarbonyl-5-O-tert-butyldimethylsilyl-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol;
(1S)-1-C-(5-N-Benzyloxymethyl-4-tert-butoxypyrrolo[3,2-d]pyrimidin-7-yl)-N-tert-butoxycarbonyl-5-O-tert-butyldimethylsilyl-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol;
(1S)-1-C-(5-N-Benzyl-4-benzyloxy-2-N,N-dibenzylaminopyrrolo[3,2-d]pyrimidin-7-yl)-5-O-tert-butyldimethylsilyl-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol; and
(1S)-1-C-{4-Benzyloxy-5-N-benzyloxymethyl-2-N,N-bis-(4-methoxybenzyl)aminopyrrolo[3,2-d]pyrimidin-7-yl}N-tert-butoxycarbonyl-5-O-tert-butyldimethylsilyl-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol.
4. A process of preparing a compound of formula (XX) as defined in claim 1 , wherein the process comprises the steps:
(a) reacting a compound of the formula (II)
wherein Z′ is a hydrogen or halogen atom, a group of formula SQ or OQ, or a triallrylsilyloxy, alkyldiarylsilyloxy or optionally substituted triarylmethoxy group, and Q is an optionally substituted alkyl, aralkyl or aryl group, sequentially with a halogenating agent and a sterically hindered base to form an imine;
(b) condensing the imine thus prepared with an anion produced by abstraction of the bromine or iodine atom from a compound of formula (XIX):
wherein R 5 is a bromine or iodine atom, R 6 is an N-protecting group, B′ and D′ are independently selected from H, OR 7 and N(R 8 ) 2 , and R 7 and R 8 are O- and N-protecting groups respectively to produce a 1-C-(pyrrolo[3,2-d]pyrimidin-7-yl)-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol derivative of formula (XX):
wherein R 9 is a hydrogen atom, Z′ is as defined above for compounds of formula (II) and R 6 , B′ and D′ are as defined above for compounds of formula (XIX);
and optionally
(c) converting R 9 from a hydrogen atom to an alkoxycarbonyl or aralkyloxycarbonyl group by reaction with an alkoxycarbonylating or aralkyloxycarbonylating reagent; or
(d) converting Z′ from a trialkylsilyloxy, alkyldiarylsilyloxy or optionally substituted triarylmethoxy group to a hydroxy group by reaction with a source of fluoride or acid.