Phosphoramide compounds

Borch etal, US Patent 6,656,926 (December 2, 2003) Assignee Purdue Research Foundation Utility Anti-Neoplastic Agent for Animals 

Lithium bis(trimethylsilyl)amide (2.50 mmol, 1.0 M in THF) was added dropwise to a solution of l,4-dimethoxy-2-hydroxymethylnaphthalene (2.29mmol) dissolved in 10 ml THF at —78°C. This was then added dropwise to a solution of bis(2-chloroethyl)phosphoramidic dichloride (2.75 mmol) dissolved in 20 ml THF, the reaction mixture stirred at —78°C 90 minutes, warmed to —20°C, and ammonia passed through the mixture 10 minutes. Thereafter, the mixture stirred an additional 10 minutes, 30 ml 2% HCl added, and then extracted 4 times with EtOAc. The combined organic layers were washed twice with saturated brine, dried, filtered, and evaporated. The mixture was purified by chromatography using methyl alcohol/EtOAc, 2 98, and the product isolated in 50% yield as a yellow oil, Rf = 0.59. H- and P-NMR data supplied. 

Beginning with l,4-dihydroxy-2-naphthoic acid the preparation of the Step 1 reagent is described by the author. 

Bromoethyl derivatives were prepared using bis(2-bromoethyl)-phosphoramidic dichloride and its preparation is provided by the author. 

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Applications of oxazaphospholidine-borane complexes, cyclic phosphoramides, compounds with N—P=0 function, and other P-heterocycles in enantio-selective catalysis 99SL377. 

Other, preferable compounds are from the class of amino phospohonates (21). The preparation of several phosphoramidate compounds has been described in detail (68). The basic route of synthesis is shown in Figure 8.3. 

This ease of synthesis of cyclic acetals makes them appropriate for the preparation of certain well-defined, mono-substituted esters of different origin. 2,3 4,5-Di-0-isopropylidene-/8-D-fructopyranose has been used for the synthesis of certain phosphoramidate compounds. The acetal is dissolved in 20 ml of toluene and refluxed for 6 to 8 hours in the presence of phosphoramidic chloride. The sirupy l-[iV,W-bis-(2-chloroethyl)phos-phoramidic chloride] (5) is then used for the preparation of other derivatives, such as the phosphoramidate itself. Hydrolysis with ethanolic hydrogen chloride removes the isopropylidene groups and results in the formation of ethyl /3-D-fructopyranoside l-[iV,JV-bis-(2-chloroethyl)phosphoramidate]. 

We are going to try to synthesize neutral phosphoramidate compounds with this and the other bulky amines. A similar feature was observed for the reaction of POCI3 with tert-butyl cydohexyl amine in CHCb under reflux condition, where the salt [NH2(ferf-... 

Another strategy for preparation of phosphoramidate compounds is the application of sodium amide salts which produces sodium halide as a by-product [82] (Scheme 4). 

A search on the CSD shows that the nitrogen atoms bound to phosphorus in phosphoramidate compounds aren t involved in normal H-bonding interaction as an acceptor due to the deviation of each N atom environment from pyramidality after binding to P and decreasing its Lewis base character with respect to the initial amine so that, merely one example (refcode HESCEO [111], Scheme 23), belonging to the diazaphosphorinane family, is observed so far with the donor...acceptor (N...N) distance of 3.258(8) A in which it may be considered as a weak N—H... N—P hydrogen bond. 

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Compound (1) phosphorylates phosphate monoesters and alcohols, although with the latter a considerable excess of alcohol is necessary to obtain satisfactory yields. In the absence of mercuric ions the milder phosphorylating species (3) can be isolated which converts monoalkyl phosphates to pyrophosphate diesters in good yield but does not react appreciably with alcohols unless catalytic amounts of boron trifluoride are added. Amine salts of (3) are converted to phosphoramidates on heating. In the presence of silver ions, O-esters of thiophosphoric acid behave as phosphorylating agents and a very mild and convenient procedure suitable for preparing labile unsymmetrical pyrophosphate diesters, such as the... 

Chloro- and A TV-dichloro-phosphoramidate esters (20) and (21) are readily prepared from the parent phosphoramidate by direct chlorination in mildly acidic solution but when R = Ph, the use of t-butyl hypochlorite is preferable, to avoid chlorination of the aromatic nucleus. These compounds behave as pseudohalogens, (21) reacting with olefinic compounds such as styrene to give (22), which is also formed by chlorination of the N-phosphorylaziridine (23). ... 

Thus the reaction product of diethyl ether and diphosphorus pentoxide, a pale yellowish syrupy mass, was designated as ethyl metaphosphate (147), other ethoxy-containing compounds give the same product 102-103) it can be reprecipitated from chloroform/ether and reacts with aniline to give the phosphoramidate 148 104) which is conceivably a trapping product of ethyl metaphosphate 147, or a cleavage product of polymeric metaphosphates. 

See Chlorine Nitrogen compounds, or Dimethyl phosphoramidate Phosphorus pentachloride Urea Sodium chloride Nitrogen compounds See other irradiation decomposition incidents... 

Pavan Kumar et al. <2006NJC717> investigated the reaction of diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) with cyclic phosphates or phosphoramides in order to determine the structural preferences in spirocyclic penta- and hexacoordinate aminophosphoranes. They found that sulfur would coordinate to phosphorus to form the [3.3.0] bicyclic compounds 94-96. 

The phosphoramidic chloride (11) has been employed to phosphorylate phenols and alcohols, including carbohydrates.16 Other activity in phosphorylation chemistry has been mostly concentrated in two main areas. In the first of these, Japanese workers have continued their studies on the use of 2-substituted-4-nitrophenyl-phosphoric acids. The 7V-protonated form of the 2-dimethylamino-compound (12 R = Me) is a better phosphorylating agent than the corresponding 2-diethylamino-compound. The reaction of (12) with hydroxy-amines results in selective O-phos-... 

When the phosphoramidic difluoride (116) reacts with diols, alkanolamines, or diamines, the manner of ring closure is dependent on n in a way which is both novel, and, from the synthetic viewpoint, potentially useful, although for compounds for which n = 2 a mixture of products (117 R = F or MeaN) may result.88... 

Mechanistically, the compounds (162 X = O or S) and (163) represent two extremes in the base hydrolysis of phosphoramidates and phosphoramidothioates the former hydrolyse in an elimination-addition (EA) process whereas for the latter the sequence is one of addition followed by elimination AE). Further exploration of... 

Phosphoramidates are organophosphorus compounds containing a P-N bond. In recent years, innovative prodrug approaches have been developed based on the cleavage of the P-N bond, two examples of which are presented here. 

A direct reaction of activation is exemplified by the NK receptor antagonist L-754,030 (9.78) developed as an i.v. drug against emesis, migraine, and chronic pain. Because the compound has a low water solubility unfavorable for i.v. administration, a phosphoramidate prodrug (9.77) has been examined [152], This compound hydrolyzed rapidly under acidic conditions. More importantly, it was rapidly converted to L-754,030 in rat blood but was... 

A few organophosphorus insecticides are also phosphoramidates, hydrolysis of the P-N bond being considered a route of detoxification. This is exemplified by the metabolism of acephate (9.82, Fig. 9.15), whose mechanisms of activation and detoxification have recently been re-examined in mice to better understand the relative innocuity of the compound in mammals and its selective toxicity in insects [156],... 

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