Verfahren zur Herstellung von Orthophosphor-saeureestern oder -esteramiden

摘要

Phosphates and phosphoramidates are prepared from organic hydroxy compounds and organic amino compounds respectively, by reacting these with organic tertiary phosphites, in the presence of a solvent, and an active methylene compound which is a bromo- or chloro-derivative of N-cyclohexyl cyanoacetamide, cyanoacetamide, malonamide, or a C1 to C4 alkyl cyanoacetate, in accordance with the following equations: (a) wherein R1 is alkyl or aralkyl; R2 and R3 are alkyl, aralkyl or aryl which may be substituted; R4 is an organic radical attached to the oxygen through a carbon atom; and X is -Cl or -Br, A is -CN or -CONH2, Y is -NH2, -NH-cyclohexyl, or OR7 and R7 is C1 to C4 alkyl; and (b) wherein R1, R2, R3, R4, X, A, and Y are as before; R5 is an organic group attached to the nitrogen through a carbon atom, and R6 is hydrogen, alkyl, aralkyl, or aryl. Typical phosphites are tri-alkyl phosphites, where alkyl is C1 to C4, tribenzyl phosphite, and monoethyl bis-(p-nitrophenyl) phosphite. Hydroxyl-group-containing compounds may be C1 to C18 aliphatic alcohols; phenols; araliphatic alcohols such as benzyl alcohol; carbohydrates such as glucose, fructose, ribose, or xylose; nucleosides such as adenosine, guanosine, inosine, uridine, or cytidine; or pyrimidino or purine nucleosides with the hydroxyl groups proteced by carbonyl, acetyl, benzyl, benzylidene or isopropylidene groups; steroids such as cholesterol, ergosterol, or testosterone; terpene alcohols such as borneal or menthol; or Vitamins A1, A2, B1, B2, B6, or C. Amino-group-containing compounds may be C1 to C18 aliphatic amines or imines, or aromatic amines such as aniline or N-substituted aniline. The reaction is carried out in a solvent inert to the enol phosphates produced by the Perkow reaction, suitably ether, benzene, dioxane, N-dimethyl formamide or tetrahydrofuran. Reaction conditions may vary from temperatures of - 50 DEG C. for 1 to 2 hours for methyl or ethyl alcohol, phenol or aniline, to room temperature for 24 to 48 hours for carbohydrates, nucleosides, vitamins, sterols or terpene alcohols. Examples are given for the preparation of triethyl phosphate; methyl-, n-propyl-, and phenyl-diethyl phosphates; diethyl-N-phenyl phosphoramidate; monoethylbis - p - nitrophenyl phosphate; diethylmono - p - nitrophenyl phosphate; dimethyl-17 - testosterone - phosphate; dibenzyl - 21-31 - 0 - isopropylidene - adenosine - 51 - phosphate which is hydrolized to adenosine-5-phosphate and purified as the barium salt; and borneoldibenzyl phosphate.