Methylphosphonates

The use of methylphosphonates (12) as antisense compounds has been reviewed by several authors [83,84]. Very good nuclease resistance and a different mechanism of membrane penetration are the most remarkable features of this ODN modification [85]. The lack of anionic charge however renders the compounds relatively insoluble in water. Drug/target duplexes do not activate RNase-H. Therefore, high concentrations of up to 100 pM are required to achieve antisense activity. Nevertheless, methylphosphonates seem to be suited elements of chimeric oligonucleotides. 

Triphosphates (13) may be formed using O-ethyl or O-isopropyl phosphoramidites. These esters do not undergo hydrolysis by concentrated aqueous ammonia solution applied for deprotection after synthesis. Another option for their synthesis involves use of 3 -0-phos-phorodimorpholidites, which are subjected to alcoholysis prior to the final oxidation step [90]. By choice of specific phosphoramidites this technology may be used to insert conjugated functional groups into an oligonucleotide. 

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Eyrol 51 is a water-soluble Hquid containing about 21% phosphoms. It is made by a multistep process from dimethyl methylphosphonate, phosphoms pentoxide, and ethylene oxide. The end groups are principally primary hydroxyl and the compound can thus be incorporated chemically into aminoplasts, phenoHc resins, and polyurethanes. Eyrol 51, or 58 if diluted with a small amount of isopropanol, is used along with amino resins to produce a flame-retardant resin finish on paper used for automotive air filters, or for backcoating of upholstery fabric to pass the British or California flammabiHty standards. 

Oligomeric Vinylphosphonate. A water-soluble oligomer, Fyrol 76 [41222-33-7] is produced by reaction of bis(2-chloroethyl) vinylphosphonate and dimethyl methylphosphonate with elimination of all the chlorine as methyl chloride (127,128). This Hquid, containing 22.5% P, is curable by free-radical initiation, on cotton or other fabrics. Nitrogen components, such as A/-methylolacrylamide or methylolmelamines, are usually included in the finish, which can be durable to multiple launderings (129,130). 

The methylphosphonates differ from the phosphodiesters and phosphorothiolates in that the methyl derivatives are uncharged and are thus less water soluble. Moreover, compared to the naturally occurring phosphodiesters, the methylphosphonates form slightly less stable duplexes with complementary DNA and RNA sequences. This effect has been ascribed to the iaevitable chiraUty problem that is, if one isomer biads less well, the overall binding is decreased. Methylphosphonates can enter cell membranes by a passive mechanism and are completely resistant to nucleases. 

Methylphosphonic acid [993-13-5] M 96.0, m 104-106 , 105-107 , 108 , pK, 2.12, pK j 7.29. If it tests for Cf, add H2O and evaporate to dryness repeat several times till free from Cl". The residue solidifies to a wax-like solid. Alternatively, dissolve the acid in the minimum volume of H2O, add charcoal, warm, filter and evaporate to dryness in a vacuum over P2O5. [J Am Chem Soc 75 3379 1953.] The di-Na salt is prepared from 24g of acid in 50mL of dry EtOH and a solution of 23g Na dissolved in 400mL EtOH is added. A white ppte is formed but the mixture is refluxed for 30min to complete the reaction. Filter off and recrystallise from 50% EtOH. Dry crystals in a vacuum desiccator. [7 Chem Soc 3292 1952.]... 

Ironically, the reactor was used to produce Antiblaze 19, a flame retardant used in textiles and polyurethane foam. Antiblaze 19 is a cyclic phosphorate ester produced from a mixture of trimethyl phosphite, dimethyl methylphosphonate (DMMP), and trimethyl phosphate (TMOP). The final product is not considered flammable, but trimethyl phosphite is moisture sensitive and flammable, with a flash point of about 27 C. 

Although most of the macrocycles that contain phosphorus or arsenic which have thus far been prepared, are primarily transition metals binders, two compounds have been prepared which are essentially crown ethers containing phosphorus. Kudrya, Shtepanek and Kirsanovhave prepared two compounds which are essentially polyoxygen macrocycles but which contain one or two methylphosphonic acid esters as part of the ring. These two macrocycles are shown below as 7d and 17 and are both prepared by the reaction of 2,2 [oxybis(ethyleneoxy)] bisphenolate with methylphosphonic dichloride in a mixture of acetonitrile and benzene. The crystalline monomer 16) and dimer 17) were isolated in 17% and 11% yields respectively as indicated in Eq. (6.13). 

Waste Handling for Unirradiated Plutonium Processing. Higher capacity, better-performing, and more radiation-resistant separation materials such as new ion exchange resins(21) and solvent extractants, similar to dihexyl-N,N-di ethyl carbamoyl methylphosphonate,(22) are needed to selectively recover actinides from acidic wastes. The application of membranes and other new techniques should be explored. 

Monoamidotriphosphate compounds have been evaluated for their combined detergent-sequestrant action [65,66]. Good surfactant properties are also attributed to organoaminodialkylenephosphonic acids. Typical compounds of this kind are the tetra- and trialkali salts of decyl-, dodecyl-, and tetradecylaminodi (methylphosphonate). Values of surface tension and detergency are given in Refs. 118 and 216-219. Wash test results, foam behavior, wetting performance, and surface tensions of aqueous solutions of phosphate esters have been tabulated [12,17,18,33,37,50,52,56,90,220]. 

Derivatives substituted on phosphorus are named by standard procedures [13, 14] e.g, / -methyl derivatives are named as methylphosphonates. 

Two methods can be used to prepare phosphonodithioacetate 28 (Scheme 7). One method consists of the addition of methyl chlorodithioformates to the cuprate of a diethyl methylphosphonate [19], the other is the addition of HCl gas and EtSH to a diethyl (cyanomethyl)phosphonate followed by a sulfhydrolysis in pyridine [20]. 

Hydrolysis products GF s hydrolysis products, hydrofluoric and cyclohexyl-methylphosphonic acids, are less toxic than their parent compound. 

Reactivity Hydrolysis products Ethyl methylphosphonic acid, 2-(Diethylamino) ethanethiol, and P,P-diethyl dimethyldiphosphonate... 

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