Nucleoside process

Claim 2

The process for preparing the 1,3,5-tri-O-acyl-2-deoxy-2-fluoroarabinofuranoside ester of Formula VI wherein R l , R 2 , and R 3 are the carbonyl attached organic groups of carboxylic acyl groups having 1 to 20 carbon atoms and selected from alkanoyl, aroyl, and substituted aroyl wherein said substituent is alkyl, alkoxy, halo, nitro, or dinitro which comprises contacting potassium acid fluoride with the ribofuranoside ester of Formula V wherein R 1 , R 2 , and R3 have the same meaning as above and R 4 is the 1-imidazosulfonyl or the -SO 2 F group in an organic liquid reaction medium at 75-170°C. until maximal production of product has occurred.

Claim 3

The process of Claim 1 wherein the liquid organic reaction medium is an alkanol, alkanpolyol, alkoxyalkanol, cyanoalkane, alkanoamide, ether, or polyether having a molecular weight of from about 30 to 200.

Claim 4

The process of Claim 1 wherein the liquid organic reaction medium is selected from the group consisting of acetonitrile, butanol, tert.-butanol, formamide, or a compound of the formula R a OAlkOR b wherein R a and R are selected from the group consisting of H, alkyl, or alkoxyalkyl each having up to 6 carbon atoms, and Alk is an alkylene group containing from up to 6 carbon atoms.

Claim 5

The process of Claim 3 wherein said liquid organic reaction medium is said mono- or diether of the formula R a OAlkOR b .

Claim 6

The process of Claim 4 wherein said liquid organic reaction medium is 2,3-butanediol.

Claim 7

The process of Claim 5 wherein the reaction temperature is 130-145°C. -

Claim 8

The process of Claim 1 when carried out in the presence of a strong acid.

Claim 9

The process of Claim 1 when carried out in the presence of hydrofluoric acid.

Claim 10

The process of Claim 6 wherein 0.5 to 2.0 moles of hydrofluoric acid per mole of potassium acid fluoride is present in the reaction mixture during the heating period.

Claim 11

The process of Claim 1 wherein the time of maximal production of product is determined by sequential analyses during the course of the reaction.

Claim 12

The process of Claim 9 wherein a reaction period of from 2 to 3 hrs. is employed.

Claim 13

The process of Claim 4 wherein ethylene glycol is employed as reaction medium.

Claim 14

The process of Claim 1 wherein said carboxylic acyl groups of the formulas are aroyl or substituted aroyl groups.

Claim 15

The process of Claim 13 wherein said carboxylic acyl groups are benzyol groups.

Claim 16

The 2-deoxy-2-fluoroarabinoside having Formula VIa wherein Ar is phenyl, naphthyl, substituted phenyl, or substituted naphthyl and said substituent contains up to 4 carbon.atoms and is selected from alkyl, alkoxyl, halo, nitro, and dinitro and the 1-a or 1-β configuration.

Claim 17

The 2-deoxy-2-fluoroarabinoside having Formula VIa wherein Ar is phenyl, naphthyl, substituted phenyl, or substituted naphthyl and said substituent contains up to 4 carbon.atoms and is selected from alkyl, alkoxyl, halo, nitro, and dinitro and the 1-a or 1-β configuration.

Claim 18

The compound of Claim 15 wherein Ar is selected from the group consisting of phenyl, tolyl, bromophenyl, chlorophenyl, nitrophenyl, and dinitrophenyl.

Claim 19

The compound of Claim 15, 2-deoxy-2-fluoro-1,3,5-tri-O-benzoylarabinofuranoside.

Claim 20

The 1,2,3,5-tetra-0-acylribofuranoside having Formula Va wherein Ar is phenyl, naphthyl, substituted phenyl, or substituted naphthyl and said substituent contains up to 4 carbon atoms is selected from alkyl, alkoxyl, halo, nitro, and dinitro, and R 4 is 1-imidazosulfonyl or -SO 2 F and the 1-a or 1-βconfiguration.

Claim 21

The 1,2,3,5-tetra-0-acylribofuranoside having Formula Va wherein Ar is phenyl, naphthyl, substituted phenyl, or substituted naphthyl and said substituent contains up to 4 carbon atoms is selected from alkyl, alkoxyl, halo, nitro, and dinitro, and R 4 is 1-imidazosulfonyl or -SO 2 F and the 1-a or 1-βconfiguration.

Claim 22

The compound of Claim 18 wherein Ar is selected from the group consisting of phenyl, tolyl, bromophenyl, chlorophenyl, nitrophenyl, and dinitrophenyl.

Claim 23

The compound of Claim 18, 1,3,5-tri-O-benzoyl-2-O-(l-imidazosulfonyl)ribofuranoside.

Claim 24

The compound of Claim 18, 1,3,5-tri-O-benzoyl-2-O-fluorosulfonylribofuranoside.

Claim 25

The 3,5-di-0-acyl-2-deoxy-2-fluoroarabinofuranosyl halide having Formula VIIa wherein X is chloro, bromo, fluoro, or iodo, and Ar is phenyl, naphthyl, substituted phenyl, or sustituted naphthyl and said substituent contains up to 4 carbon atoms and is selected from alkyl, alkoxyl, halo, nitro, and dinitro and the 1-aor 1-β configuration.

Claim 26

The 3,5-di-0-acyl-2-deoxy-2-fluoroarabinofuranosyl halide having Formula VIIa wherein X is chloro, bromo, fluoro, or iodo, and Ar is phenyl, naphthyl, substituted phenyl, or sustituted naphthyl and said substituent contains up to 4 carbon atoms and is selected from alkyl, alkoxyl, halo, nitro, and dinitro and the 1-aor 1-β configuration.

Claim 27

The compound of Claim 22 wherein Ar is selected from the group consisting of phenyl, tolyl, bromophenyl, chlorophenyl, nitrophenyl, and dinitrophenyl, and X is bromo.

Claim 28

The compound of Claim 23, 2-deoxy-2-fluoro-3,5-di-O-benzoylarabinofuranosyl bromide.

Claim 29

The arabinofuranosyl nucleoside derivative having Formula VIIIa wherein A is OH or NH 2 , B is 0 or S, Y is halogen, amino, monoalkylamino (C 1-4 ), monoaralkylamino (C 7-20 ), dialkylamino (C 2-8 ), aminomethyl, hydroxymethyl, lower alkyl (C 1-4 )' phenyl, naphthyl, aralkyl (C7-20), vinyl, or ethynyl, Z is N or methyne, and Ar is phenyl, naphthyl, sustituted phenyl, or substituted naphthyl and said substituent contains up to 4 carbon atoms and is selected from alkyl, alkoxyl, halo, nitro, and dinitro.

Claim 30

The arabinofuranosyl nucleoside derivative having Formula VIIIa wherein A is OH or NH 2 , B is 0 or S, Y is halogen, amino, monoalkylamino (C 1-4 ), monoaralkylamino (C 7-20 ), dialkylamino (C 2-8 ), aminomethyl, hydroxymethyl, lower alkyl (C 1-4 )' phenyl, naphthyl, aralkyl (C7-20), vinyl, or ethynyl, Z is N or methyne, and Ar is phenyl, naphthyl, sustituted phenyl, or substituted naphthyl and said substituent contains up to 4 carbon atoms and is selected from alkyl, alkoxyl, halo, nitro, and dinitro.

Claim 31

The compound of Claim 25 wherein A is OH, Y is I, Z is methyne, and Ar is phenyl, naphthyl, substituted phenyl, or substituted naphthyl and said substituent contains up to 4 carbon atoms and is selected from alkyl, alkoxyl, halo, nitro, and dinitro.

Claim 32

The compound of Claim 26, 1-(3,5-di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl]-5-iodouracil.

Claim 33

In a process for preparing the arabinofuranosyl nucleoside derivative having Formula IX wherein A is OH or NH 2 , B is O or S, Y is halogen, amino, monoalkylamino (C 1-4 ), monoaralkylamino (C 7-20 ), dialkylamino (C 2-8 ), aminomethyl, hydroxymethyl, lower alkyl (C 1-4 ), phenyl, naphthyl, aralkyl (C 7 - 20 ), vinyl, or ethynyl, and Z is N or -C=, the improvement which comprises converting the 1,3,5 - tri-0- acylribofuranoside of Formula IV into the corresponding ribofuranoside ester of Formula V wherein R 1 , R 2 , and R 3 are the carbonyl attached organic groups of carboxylic acyl groups having 1 to 20 carbon atoms and selected from alkanoyl, aroyl, and substituted aroyl wherein said substituent is alkyl, alkoxy, halo, nitro, or dinitro, and R 4 is 1-imidazosulfonyl or the -SO 2 F group; thereafter causing the ester of Formula V-to react in the presence of potassium acid fluoride in an organic liquid reaction medium at 75-170°C until maximal production of the compound of Formula VI has occurred; thereafter causing the compound of Formula VI to react with hydrogen chloride, hydrogen bromide, or hydrogen fluoride under non-hydrolytic conditions to produce the compound of Formula VII wherein R 1 and R 2 are as previously defined, and X is chlorine, bromine, or fluorine thereafter causing the compound of Formula VII to react with the fully silylated derivative of the pyrimidine of the following formula to produce the compound of Formula VIII wherein R 1 , R 2 , A, B, and Y are as previously defined; and thereafter converting the compound of Formula VIII to the compound of Formula IX by hydrolysis.

Claim 34

In a process for preparing the arabinofuranosyl nucleoside derivative having Formula IX wherein A is OH or NH 2 , B is O or S, Y is halogen, amino, monoalkylamino (C 1-4 ), monoaralkylamino (C 7-20 ), dialkylamino (C 2-8 ), aminomethyl, hydroxymethyl, lower alkyl (C 1-4 ), phenyl, naphthyl, aralkyl (C 7 - 20 ), vinyl, or ethynyl, and Z is N or -C=, the improvement which comprises converting the 1,3,5 - tri-0- acylribofuranoside of Formula IV into the corresponding ribofuranoside ester of Formula V wherein R 1 , R 2 , and R 3 are the carbonyl attached organic groups of carboxylic acyl groups having 1 to 20 carbon atoms and selected from alkanoyl, aroyl, and substituted aroyl wherein said substituent is alkyl, alkoxy, halo, nitro, or dinitro, and R 4 is 1-imidazosulfonyl or the -SO 2 F group; thereafter causing the ester of Formula V-to react in the presence of potassium acid fluoride in an organic liquid reaction medium at 75-170°C until maximal production of the compound of Formula VI has occurred; thereafter causing the compound of Formula VI to react with hydrogen chloride, hydrogen bromide, or hydrogen fluoride under non-hydrolytic conditions to produce the compound of Formula VII wherein R 1 and R 2 are as previously defined, and X is chlorine, bromine, or fluorine thereafter causing the compound of Formula VII to react with the fully silylated derivative of the pyrimidine of the following formula to produce the compound of Formula VIII wherein R 1 , R 2 , A, B, and Y are as previously defined; and thereafter converting the compound of Formula VIII to the compound of Formula IX by hydrolysis.