13086-84-5Relevant articles and documents
Di- tert-butyl Phosphonate Route to the Antiviral Drug Tenofovir
Dietz, Jule-Philipp,Ferenc, Dorota,Jamison, Timothy F.,Gupton, B. Frank,Opatz, Till
, p. 789 - 798 (2021/03/01)
Di-tert-butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di-tert-butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent. For the synthesis of tenofovir, a two-step sequence was developed using Mg(OtBu)2 as the base for the alkylation of (R)-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di-tert-butoxyphosphoryl)methyl methanesulfonate showed to be the most efficient electrophile tested, affording PMPA in 72% yield on a 5 g scale. The developed protocol could also be applied for the preparation of the hepatitis B drug adefovir (64% yield/1 g scale).
Method for preparing phosphite diester by transesterification
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Paragraph 0028, (2020/01/25)
The invention discloses a method for preparing phosphite diester by transesterification. Dimethyl phosphite and monohydric alcohol which are used as raw materials are stirred, reacted and rectified under the action of a basic catalyst to prepare the phosphite diester, so the problems of high deice requirements and large amount of acid-containing three wastes in the process of producing the phosphite diester by reacting phosphorus trichloride with alcohol are avoided. The method has the advantages of low raw material toxicity, simple process, mild reaction conditions, low device requirements, low pollution, high raw material conversion rate, high product selectivity, stable supply of the raw materials, provision of the phosphite diester used for fine chemical engineering or medical intermediates by dimethyl phosphite production enterprises, high added values of the product, and provision of a new way for the synthesis of the phosphite diester.
Development of efficient processes for the preparation of Di-tert-butyl potassium phosphate and Di-tert-butyl (Chloromethyl) phosphate
Zheng, Bin,Fox, Richard J.,Sugiyama, Masano,Fritz, Alan,Eastgate, Martin D.
, p. 636 - 642 (2014/06/09)
A new and efficient process to prepare di-tert-butyl (chloromethyl) phosphate, a key compound in the formation of many phosphon-oxymethyl pro-drugs, from chloromethyl chlorosulfate (CMCS) and di-tert-butyl potassium phosphate (DTBPP) is described. To develop a process to this important compound with overall efficiency, an improved synthesis of DTBPP was required. The two-step process to DTBPP starts from PCl3 and leverages a H2O 2/catalytic KI mediated oxidation of di-tert-butyl phosphite to provide DTBPP in 81% yield and high purity. In the development of the new process to di-tert-butyl (chloromethyl) phosphate, a comparison to the corresponding tosylate derivative was made. A rational selection of base, phase-transfer catalyst (PTC), and stabilizing additive minimized CMCS decomposition and led to an optimized yield (90% solution yield), improved product purity, and identification of a technique to enable the long-term storage of di-tert-butyl (chloromethyl) phosphate.
PI-3 KINASE INHIBITOR PRODRUGS
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Page 81, (2010/02/09)
The invention provides novel prodrugs of inhibitors of PI-3 kinase. The novel compounds are LY294002 and analogs thereof comprising a reversibly quaternized amine.
Thermal Retro-Trimerization of Some 1,3,5,2,4,6-Trioxatriphosphorinanes to Phosphenites
Quin, Louis D.,Ionkin, Alexey S.
, p. 5186 - 5189 (2007/10/02)
Pyrolysis in a packed tube of the vapor from three 2,4,6-tris(aryloxy)-1,3,5,2,4,6-trioxatriphosphorinanes was performed at 300-350 deg C and 1E-6 mm; the product was collected on a cold finger chilled by liquid nitrogen.The cracking of the trimer was complete, and the product at -195 deg C appeared to consist only of the monomeric aryl phosphenite, ArOP=O.On warming, dimerization occured, later followed by trimer formation.The weak 31P NMR signal for the phosphenite (about δ 238 for three O-aryl derivatives) persisted in the solution for several weeks if water was rigorously excluded.Treatment of the phosphenite with water or alcohols at -195 deg C gave a mixture of products; the major product (ArO-PH(O)OH) came from addition of the nucleophile to the P=O bond, but significant amounts (10-20percent) of dialkyl H-phosphonates (HP(O)(OR)2) were present, apparently from displacement of the O-aryl substituent of the phosphenite, followed by addition to the double bond.
Bis(dialkylamino)phosphines
King, R.B.,Sundaram, P.M.
, p. 1784 - 1789 (2007/10/02)
Reactions of LiAlH4 with sufficiently sterically hindered (R2N)2PCl derivatives (R = isopropyl and ethyl but not methyl) in diethylether give the corresponding (R2N)2PH derivatives as air-sensitive, vacuum-destillable liquids.Analogous reactions of LiAlH4 with sufficiently sterically hindered heterocycles (CH2)n(NR)2PCl (R = tert-butyl, n = 2 and 3; R not methyl, n not 2) give the corresponding heterocyclic PH derivatives (CH2)n(NR)2PH.The dialkylamino groups in (R2N)2PH undergo successive alcoholysis with the alcohols R'OH (R' = methyl, ethyl, isopropyl, andtert-butyl) to form (R2N)(R'O)PH and (R'O)2PH derivatives, which are identified by their phosphorus-31 NMR spectra.The derivatives (R2N)(R'O)PH (R = isopropyl; R'= methyl, ethyl, isopropyl, and tert-butyl) can be isolated by vacuum distillation as air-sensitive liquids, but the derivatives (R'O)2PH generally decompose upon attempted vacuum distillation.The (R2N)2PH derivatives undergo base-catalyzed addition to (R2N)2PCH=CH2 to give the corresponding diphosphines (R2N)2PCH2CH2P(NR2)2, provided that the R2N groups are not too bulky .The mass spectra and NMR spectra of the new organophosphorus compounds are described.
