Phosphorochloridic acids, preparation

Although the phosphorochloridic acids are, in principle, related as in (5.263), they are more difficult to isolate than their fluoro analogues. Phosphorodichloridic acid can be prepared by the hydrolysis of pyrophosphoryl chloride at -60°C (5.279) or from phosphoryl chloride and water (5.280). It is a clear liquid, stable in the absence of air and has a melting point of -18°C. 

In preparation for the eventual removal of the undesired oxygen function at C-10 of 313 via a Birch reduction, the phenol 313 was phosphorylated with diethyl phosphorochloridate in the presence of triethylamine to give 314, which underwent stereoselective reduction with sodium borohydride with concomitant N-deacylation to deliver the amino alcohol 315. N-Methylation of 315 by the Eschweiler-Clarke protocol using formaldehyde and formic acid followed by ammonolysis of the ester group and acetylation of the C-2 hydroxyl function afforded 316. Dehydration of the amide moiety in 316 with phosphorus oxychloride and subsequent reaction of the resulting amino nitrile 317 with LiAlH4 furnished 318, which underwent reduction with sodium in liquid ammonia to provide unnatural (+)-galanthamine. 

Phosphorus oxychloride is a suitable reagent for preparation of the symmetrically substituted phospho-triesters of type (RO)3PO. The preparation is easily achieved by treatment of phosphorus oxychloride with 3 equiv. of alcohols or their metal salts. The reaction is generally promoted by a base or acid. Titanium trichloride is a particularly effective catalyst for the reaction. Conversion of POCI3 to unsymmetri-cally substituted phosphotriesters is achievable with difficulty. Phosphorochloridates and phosphorodichloridates have been used for the preparation of mixed tertiary phosphoric esters of type (ROlmPOfOROn (ffi = 1, n = 2, or m = 2, n = 1) in a very wide variety. Reaction of phosphorus oxychloride and 1 or 2 equiv. of alcohols followed by hydrolysis forms phosphomonoesters or phosphodi-esters, respectively. The hydrolysis may be generally effected by dilute aqueous alkali. Some phosphoFodichlori te intermediates are easily hydrolyzed by water. For example, the phosphorylation of a ribonucleoside (1 equation 4) with phosphorus oxychloride in an aqueous pyridine-acetonitrile mixture furnishes the nucleoside S -monophosphate (2) in excellent yield. ... 

When 5 -0-tritylthymidine-3 -phosphate is treated with excess tri-isopropyl benzenesulphonylchloride (TPS) and thymidine, and then deprotected, the trinucleoside monophosphate (7a) is obtained. The 5-bromo- and 5-fluoro-deoxyuridine analogues (7b) and (7c) are prepared similarly. All are resistant to snake venom and spleen phosphodiesterases, and hydrolyse too slowly under physiological conditions for the cytotoxic moiety to be effective. When protected UpU is treated with bis-(4-nitrophenyl) phosphorochloridate, and subsequently with an amine or amino-acid ester, the dinucleoside phosphor-amidates (8) are formed. Although the compounds investigated split the P—N bond under the conditions required for protecting-group removal, the method has potential for the preparation of easily fissionable neutral phospho-triesters. 

Scheme 6 illustrates the use of these protecting groups in the phosphorylation of 2 -deoxynucleosides by Michelson and Todd. 5 -0-Trityl-thymidine (110) was phosphorylated with dibenzyl phosphorochloridate (44) to (111), which, after treatment with 80% acetic acid, afforded thymidine 3-(benzyl phosphate) (112). Catalytic hydrogenolysis of (112) gave thymidine 3 -phosphate. Acetylation of (110) yielded the 3 -acetate (114) which, on detritylation to (115), followed by phosphorylation, catalytic reduction, and deacetylation, gave thymidine 5 -phosphate (116), identical with the thymidylic acid obtained by enzymic hydrolysis of 2 -deoxyribonueleic acid. A rather similar sequence was applied to the preparation of the 2 -deoxycytidine analogs of (113) and (116). 

The structure, lividomycin 5"-phosphate, was furthermore proved by chemical synthesis. Penta-N-(benzyloxycarbonyl) lividomycin A was prepared from lividomycin A by the usual Schotten-Baumann procedure in a yield of 95% it had m.p. 135-150° (dec.). Acetonation with 2,2-dimethoxypropane in N,N-dimethylformamide in the presence of p-toluenesulfonic acid at 110° for 4 hours afforded the tri-O-isopropylidene derivative of N-(benzyloxycarbonyl)lividomycin A in 49% yield m.p. 129-133° (dec.). Phosphorylation of the sole primary hydroxyl group in the D-ribose moiety of -(benzyloxycarbonyl) lividomycin A with diphenyl phosphorochloridate in dry pyridine gave penta-N-(benzyloxy-... 

Titanium tetrachloride is an efficient reagent for the conversion of trialkyl phosphites and dialkyl hydrogen phosphonates into dialkyl phosphorochloridates. Imidazolides and dialkyl or diaryl phosphoric acids react with acyl fluorides - benzoyl fluoride and oxalyl difluoride being the reagents of choice - to give quantitative yields of the phosphoryl fluorides. The procedure is adaptable to the preparation of fluorides of carbohydrate phosphates in this field, the reaction between the ceu bohydrate and tris-l//-imidazolylphosphine oxide or sulphide with the replacement of one imidazole... 

The parent phenylphosphoramidic acid, PO(NHPh)(OH)2, was obtained by a method which consisted in the ready hydro-genolysis of dibenzyl phenylphosphoramidate. An attempt to prepare dibenzyl p-dimethylaminophenylphosphoramidate by the action of iViV -dimethyl-p-phenylenediamine on dibenzyl phosphorochloridate gave only an oil. When, however, a mixture of the amine, dibenzyl hydrogen phosphite, and trichloro-bromomethane was used, a good yield of the dibenzylp-dimethyl-aminophenylphosphoramidate was obtained. It is a crystalline solid which causes severe dermatitis the irritation develops slowly and with some individuals persists for weeks. 

Esters of pyrophosphorous add can be prepared by using sodium dialkyl phosphite and a dialkyl phosphorochloridite (5.321). If a phosphorochloridate ester is used, an ester of hypophosphoric acid is obtained (5.322). 

General. Pyridine is distilled from p-toluenesulfonyl chloride and then from calcium hydride and stored over potassium hydroxide. N,N-Di-methylformamide is distilled from calcium hydride and stored over molecular sieves. Dioxane is distilled from phosphorus pentoxide. Tri-n-butylamine, triethylamine, diphenyl phosphorochloridate, and o- and p-fluorobenzoyl chlorides are distilled before use. Tri-n-butylammonium pyrophosphate is prepared at room temperature according to the method of Moffatt and Khorana and stored at 5°. Paper chromatography is carried out by the descending technique on Whatman No. 1 paper in (A) isobutyric acid-1 M NH4OH (60 40) and (B) 1-propanol-water (7 3). Electrophoresis is carried out on Whatman No. 1 paper at pH 3.5 in 0.035 M citric acid-0.0148 M sodium citrate (1 1). Evaporations are carried out under reduced pressure at bath temperatures below 30°. Phosphate analyses of nucleoside triphosphates are performed by the method of Lowry and Lopez after treatment of approximately 1 / mole of these compounds for 60 min at 22° in 1 ml of Tris chloride at pH 10.4 containing 0.02 mg of alkaline phosphatase of calf intestinal mucosa (type VII, Sigma Chemical Co.). 

Interconversion of Carboxylic Acid Derivatives. Diethyl phosphorochloridate is useful for activation of carboxylic acids toward nucleophilic attack. Subsequent treatment of the phosphate ester with thallium sulfides produced thiol esters." Variations"" on this theme included prior formation of a heterocyclic phospho-nate followed by treatment with alcohols, amines, or thiols, thus providing a racemization-free method to prepare esters, amides, and thiol esters, respectively (eq 9),""" ... 

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