Реакция #53950

Уравнение реакции

uracil

1-[5-[Bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-3,4-bis-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-2-yl]-1H-pyrimidine-2,4-dione

para-methoxybenzyl chloride

benzyloxymethyl chloride

→

1-[(2R,3R,4R,5R)-3,4-bis{[tert-Butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-(4-methoxybenzyl)-2,4(1H,3H)-pyrimidinedione

Условия реакции

Обработка

1. 1
   Другоеthe protecting group of the primary alcohol is removed by treatment with an acid such as benzenesulfonic acid at low temperature such as 0° C.

Методика

Scheme 1 shows a route for the preparation of compound of formula 2a. By using the literature known procedures (Myers, A. G.; Gin, D. Y.; Rogers, D. H., J. Amer. Chem. Soc., 1994, 116, 4697-4718), a primary alcohol of commercially available uridine is protected by treatment with an agent such as 4,4′-dimethoxytrityl chloride at room temperature in an anhydrous solvent such as anhydrous tetrahydrofuran, followed by treatment with a silylating agent such as trialkylsilyl chloride, alkylarylsilyl chloride or triarylsilyl chloride to protect two secondary alcohols at the 2- and 3-positions to form the disilyl ether. tert-Butyldimethylsilyl chloride is chosen to provide stable silyl ethers, 1-[5-[Bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-3,4-bis-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-2-yl]-1H-pyrimidine-2,4-dione. The nitrogen of the uracil is protected with an agent such as para-methoxybenzyl chloride or benzyloxymethyl chloride at low temperature such as 0° C., and the protecting group of the primary alcohol is removed by treatment with an acid such as benzenesulfonic acid at low temperature such as 0° C., to provide an alcohol, 1-[(2R,3R,4R,5R)-3,4-bis{[tert-Butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-(4-methoxybenzyl)-2,4(1H,3H)-pyrimidinedione. Treatment of the primary alcohol with an oxidation condition such as swern's condition [dimethylsulfoxide, oxalyl chloride, triethylamine, methylene chloride] provides the corresponding aldehyde. Reaction of the aldehyde with an anion of N,N-diprotected glycine ester such as tert-butyl 2-(dibenzylamino)-propanoate which is derived by treatment with lithium diisopropylamide in an anhydrous solvent such as tetrahydrofuran at low temperature such as −78° C. to −30° C. provides a mixture of two diastereomers of tert-butyl 3-[3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-2-(dibenzylamino)-3-hydroxy-propanoate. Two diasteroisomers can be separated by routine chromatography using silica gel flash column. The protecting groups PG1 and PG2 of each diastereomer such as benzyl groups can be removed by catalytic hydrogenation using a catalyst such as 5-10% palladium on carbon or 10% palladium hydroxide in a solvent such as methanol or ethanol under hydrogen atmosphere, to provide the corresponding free amine of compound of formula 2a. The absolute configration of each diastereomer is determined by X-ray analysis of the para-nitrophenylurea derivative of each diasteromer as (1R,2R,3R,4R,5R,6S) and (1R,2R,3R,4R,5S,6S).

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