Patent GB-1170933-A (GB)
Title: Improvements in or relating to the Production of 2',3'-Protected Nucleosides and their subsequent Phosphorylation
IPC: C07D233/66
Filed: 1966-10-31
Abstract: 1,170,933. 2<SP>1</SP>-3<SP>1</SP>-Blocked ribonucleosides and their phosphorylation. KYOWA HAKKO KOGYO CO. Ltd. 31 Oct., 1966 [1 Nov., 1965; 30 Nov., 1965], No. 48716/66. Addition to 1,056,428. Heading C2C. A 2<SP>1</SP>,3<SP>1</SP>-O,O-disubstituted ribonucleoside is obtained by reacting a ribonucleoside with an aldehyde or ketone capable of forming a dioxolan with the ribonucleoside in the presence of a monoester of phosphorothiolic acid having the -SH group esterified as a catalyst. The monoester may be one of the formula: R.S.P(O)(OH) 2  in which R is an alkyl or aryl group either of which may be substituted by NO 2  or CN, or is a cycloalkyl, alkenyl, or alkynyl group or an aralkyl group which may be substituted with a nitro group. The process may be suitably applied to guanosine, adenosine, inosine, xanthosine, cytidine, uridine, nicotinamide, ribonucleoside, 5-amino-4-imidazole-carboxamide ribonucleoside or 5-amino- 4-imidazole-carboxamidine ribonucleoside. The aldehyde or ketone may be aliphatic, alicyclic or aromatic, e.g. acetone, diethyl ketone, methyl ethyl (propyl, isobutyl, octyl or cyclobutyl) ketones, chloroacetone, propionaldehyde, butyraldehyde, p-tolualdehyde, benzaldehyde or phenyl acetaldehyde or a cyclic ketone, e.g. cyclopentanone. The reaction may be carried out in the presence of a solvent and a dehydrating agent is desirably added to entrain water, suitable dehydrating agents being compounds having a double bond conjugated with a CO group, e.g. mesityl oxide or benzalacetone; compounds having a triple bond, e.g. diphenylacetylene; compounds having an alkoxy radical and double bond on the same C atom, e.g. 2-methoxy (or ethoxy) propylene; compounds having two alkoxy groups on the same carbon atom, e.g. acetals and ketals; cyclic ethers, e.g. ethylene oxide or propylene oxide; and ortho esters, e.g. ethyl orthoformate or ethyl orthoacetate. The blocked nucleoside product may be selectively phosphorylated at the 51-position without separation of the blocked nucleoside and the monoester of phosphorothiolic acid and the latter can be used as the phosphorylating agent by the addition of a suitable condensing agent, e.g. a carbodiimide, diimidazole, keteneimide, cyanamide, nitrile, enamine, isocyanate, isoxazole or ketene and a suitable organic amine base, e.g. pyridine or derivative thereof, triethylamine, tripropylamine or tributylamine, any solvent used in the blocking reaction being generally removed prior to the phosphorylation step. The resulting phosphorylated product contains a QSP(O) OH-O- group in the 51-position (Q being an ester-forming group, e.g. as defined above for R) and the product may be hydrolysed at room temperature to convert the QS group into an OH group followed by hydrolysis with acid or alkali to remove the protective group. In a modification the phosphorylated product is oxidized with e.g. a halogen or hydrogen peroxide and the oxidized derivative hydrolysed. Other phosphorylating agents may also be included in the phosphorylation reaction step and the ribonucleoside 5<SP>1</SP>-phosphate product may be isolated in the form of a salt.