Methylphosphonate diesters

The reaction of cycloheptaamylose with diaryl carbonates and with diaryl methylphosphonates provides a system in which a carboxylic acid derivative can be directly compared with a structurally analogous organo-phosphorus compound (Brass and Bender, 1972). The alkaline hydrolysis of these materials proceeds in twro steps, each of which is associated with the appearance of one mole of phenol (Scheme Y). The relative rates of the two steps, however, are reversed. Whereas the alkaline hydrolysis of carbonate diesters proceeds with the release of two moles of phenol in a first-order process (kh > fca), the hydrolysis of methylphosphonate diesters proceeds with the release of only one mole of phenol to produce a relatively stable aryl methylphosphonate intermediate (fca > kb), In contrast, kinetically identical pathways are observed for the reaction of cycloheptaamylose with these different substrates—in both cases, two moles of phenol are released in a first-order process.3 Maximal catalytic rate constants for the appearance of phenol are presented in Table XI. Unlike the reaction of cycloheptaamylose with m- and with p-nitrophenyl methylphosphonate discussed earlier, the reaction of cycloheptaamylose with diaryl methylphosphonates... 

It is also important to ensure that the pH of the final waste solution remains basic. If the pH is below 7, fluoride ions can react with methylphosphonate diesters, a common impurity in these agents, to regenerate the nerve agent. 

A number of methods for the stereoselective syntheses of dinucleoside methyl-phosphonates have been described. A method applicable to the large scale synthesis involves the initial preparation of methanephosphonoanilidates 62 which can be separated by silica chromatography. These are subsequently converted into the methylphosphonate diesters 63 which may be converted stereospecifically into the dinucleoside methylphosphonates 64 upon reaction with a 3 -0-protected nucleoside in the presence of DBU and lithium chloride. In an alternative method, the two diastereomeric methylphosphonates 65 can be separated and subsequently coupled with a 3 -0-protected nucleoside in the presence of an alkoxymagnesium chloride. ... 

Phosphonous esters are produced from methylphosphonous dichloride and silyl esters (6.172). Interchange of groups occurs with methylphosphonous diesters at ice temperatures (6.173). 

Methylene bis phosphinates (6.745e), with a central carbon chain, can be obtained from methyl phosphinic esters (6.253), or from methylphosphonous diesters, which, like phosphites, undergo Arbusov rearrangements with condensation (6.749). Methylene bis phosphinic acid can be obtained by reaction (6.750). This compound is reasonably stable in hot water, but on boiling it eventually gives methylene bis phosphonic acid, (H0)20P-CH2-P0(0H)2 [7]. 

Potential energy surfaces for nucleophilic displacements at phosphorus in dimethyl methyl-, chloromethyl-, dichloromethyl-, and trichloromethyl-phosphonates were computed by DFT methods. The results revealed that sequential introduction of chlorine substituents at the methyl group of a methylphosphonate diester increased the stability of TSs and intermediates leading to P-C bond cleavage. Indeed, the trichlorinated analogue (23) reacted with NaOMe exclusively via P-C bond dissociation to form dichlorocarbene, which was trapped by various alkenes to form the corresponding gem-dichlorocyclopropanes (24) (Scheme... 

An estimate of the rate enhancement associated with the intramolecular phosphorylation can be made by using isopropyl p-nitrophenyl methyl-phosphonate as a model for the covalent intermediate formed in the initial step of the reaction of cycloheptaamylose with bis (p-nitrophenyl) me thy 1-phosphonate. The first-order rate constant for the alkaline hydrolysis of isopropyl p-nitrophenyl methylphosphonate at pH 9.86 can be obtained from the data of van Hooidonk and Groos (1970) kun = 1.4 X 10-5 sec-1. This value may be compared with the maximal rate constant for the reaction of cycloheptaamylose with bis(p-nitrophenyl) methylphosphonate— k2 = 1.59 X 10-1 sec-1 at pH 9.86—which must be a minimal value for the rate of the intramolecular phosphorylation. This comparison implies a kinetic acceleration of at least 104 which is similar to rate enhancements associated with the formation of cyclic phosphates from nucleoside phosphate diesters. 

The arbitrary name VX relates to a group of D,5-diesters of methylphosphonic acid ROPO(CH3)S(CH2)2N(Rl)2. D-Isobutyl 5-2-(diethylamino)ethyl methylphosphonothioate (R= /Bu, R1 = Et), produced since 1972 exclusively in the former Soviet Union, was generally referred to as Russian VX or RVX (CAS 159939-87-4). The synonyms are VR VA phosphonothioic acid methyl-, 5-[2-(diethylamino)ethyl] D-(2-methylpropyl) ester D-isobutyl5-2-(diethylamino)ethyl methylthiophosphonate D-isobutyl 5-(W-diethylaminoethyl) methylphosphonothioate and Russian V-gas. The brutto formula of RVX is C11H26SNPO2 (MW 276.37). The stmctural formula of RVX is presented in Figure 7.1. 

The synthesis of novel HBV-specific antiviral agents, the 2-amino-6-arylthio-9-[2-(phosphonomethoxy)ethyl]purine bis (2,2,2-trifluoroethyl) esters (87a-r) has been reported. These phosphonate diesters were prepared by the reaction of substituted purines with bis-(trifluoroethyl) (2-iodoethoxy)methylphosphonate in the presence of DBU. ... 

The l-(trimethylsilyl)methylphosphonic dichloride is prepared in large scale, but in modest yield (31%), by reaction among (chlorometliyl)trimethylsilane, phosphorus trichloride, and aluminum trichloride followed by hydrolysis with a limited amount of water. Although this procedure gives moderate yields, the large number of phosphonic diesters subsequently prepared in fair to good yields (40-71%) by alcoholysis of l-(trimethylsilyl)methylphosphonic dichloride is compensatory (Scheme 2.3). 5 ... 

A related process consists initially in the reaction between diethyl methylphosphonate carbanion and a nitrile, RCN, to give the species 318, and the alkylation (R = Me, CH2CH=CH2, CH2Ph) of the latter. Work-up of the product under basic conditions leads to the enamines 319. Work-up with acid conditions affords the (2-oxoalkyl)phosphonic diesters 320 the latter were also obtained through acidolysis (3 m H2SO4) of the enamines 319. A wide choice of alkylating species is possible alkyl halides, disulphides RSSR (R = Me or Ph), sulphenyl chlorides RSCl (R = Me or Ph), PhSeBr, MeS02SMe and PhSOoCl have all been used ". ... 

As indicated above, (j5-hydroxyalkyl)phosphonic diesters can be obtained by protonation of the ions 154 under carefully controlled conditions, and the formation of such products (unaccompanied by an alkene) has been observed directly in the interaction of benzophenone and the anion from diethyl methylphosphonate, and also from dialkyl (prop-2-enyl)phosphonate anions and aldehydes under kinetic control The ionic intermediates, such as 154 (Z = Ph, CN or COOEt) from PhCHO, are stabilized in the presence of lithium or magnesium ions, so aiding in the isolation of the corresponding hydroxyalkyl)phosphonic diesters The addition of KOBu to 154b, prepared by an independent route, produces the orange colour characteristic of the ions from 153 more-... 

The treatment of diethyl (trichloromethyl)phosphonate with BuLi in thf affords diethyl [lithio(dichloromethyl)]-phosphonate the latter undergoes reactions with aldehydes or ketones to give, not only dichloroalkenes, C12C=CR R but also, from RCHO, the saturated esters RCH=CAB (A, B = Cl or P03Et2) The products from the interaction of the (l-haloalkyl)phosphonic diesters, (EtO)2P(0)CHXR (X = Cl, Br or I R = H or Me) and alk-1-enes, H2C=CHR (R = pentyl, OEt, OBu, OAc, CN or Ac) under free radical conditions, are mixtures containing moderate amounts of the esters 658 and 659, as well as diethyl methylphosphonate, in relative amounts which depend on reaction conditions " ... 

The phosphonamidite reagents needed to synthesize methylphosphonate oligonucleotides are commercially available. The standard procedures used for the synthesis of phosphodiester oligonucleotides work poorly for methylphosphonate synthesis, particularly at >l- jmol scale. There are two primary factors that account for the poor efficiency of methylphosphonate synthesis. First, NMR studies have shown that the methylphosphonite P(III) diester intermediate is more susceptible to hydrolysis by tetrazole, the capping reagent, and water compared to the phosphite diester intermediate see Fig. 1 for a schematic of the synthesis cycle and degradative side reactions). For this reason, it is necessary to ... 

Diester oxidizer. (Standard mixture available from several sources. Used to couple a 5 -diester linkage to the methylphosphonate oligonucleotide—optional.)... 

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