- 83. Nucleotide Coupling in Reverse Micelles
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Nucleotide coupling was investigated in reverse micelles formed by (cetyl)trimethylammonium bromide (CTAB), in hexane/pentan-1-ol.In particular, the coupling of 2'-deoxy-5'-O-methylcytidine 3'-O-phosphate, prepared by phosphoramidite chemistry, with 5'-amino-5'-deoxythymidine was studied in the presence of a H2O-soluble carbodiimide at w0 = 11 and 22 (w0 = /).The effect of w0 on the reaction rate was investigated.A solid-phase strategy was developed for the synthesis of 2'-deoxy-5'-O-methyl-cytidyl-(3'-5')-5'-amino-5'-deoxythymidine.The nucleotide coupling yielding the expected product occurred readily in reverse micelles, and this is discussed in connection with the micelle self-replication program.
- Boehler, Christof,Bannwarth, Willi,Luisi, Pier Luigi,Giustini, Mauro
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Read Online
- Voriconazole phosphorylcholine ester inner salt key intermediate and preparation method thereof
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The invention relates to the field of pharmaceutical chemical production, and discloses a voriconazole phosphorylcholine ester inner salt key intermediate and a preparation method thereof. The preparation method comprises the following two methods: a method A of taking ionized choline as an initial raw material, and then reacting with voriconazole to obtain a voriconazole phosphorylcholine ester inner salt key intermediate II, or a method B of reacting di(diisopropylamino)2-cyano ethoxylated phosphorus serving as an initial raw material with voriconazole, and condensing with ionized choline to obtain a voriconazole phosphorylcholine ester inner salt key intermediate II. The method is short in synthesis route, simple to operate, capable of remarkably inhibiting by-products, high in product purity and suitable for industrial production.
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Paragraph 0048-0052
(2021/06/22)
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- Voriconazole phosphorylcholine ester inner salt intermediates, preparation method and method for preparing voriconazole phosphorylcholine ester inner salt
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The invention relates to the field of pharmaceutical chemicals, and discloses a plurality of voriconazole phosphorylcholine ester inner salt intermediates, voriconazole phosphorylcholine ester inner salts and a preparation method thereof, and the preparation method specifically comprises the following steps: carrying out oxidation reaction on a compound as shown in a formula II to prepare a compound as shown in a formula IV; dissolving the intermediate shown in the formula IV in a reaction solvent, and controlling the temperature to react for a certain time; then adding a hydrolytic agent, and purifying to obtain a voriconazole phosphorylcholine ester inner salt intermediate V shown as a formula V; and preparing the voriconazole phosphorylcholine ester inner salt as shown in the formula I from the intermediate as shown in the formula V under the action of an acid-binding agent. The obtained intermediates are good in purity and high in yield; the finally prepared voriconazole phosphorylcholine ester inner salt finished product is high in yield, and the purity is up to 99.5% or above; the preparation method of the intermediate is simple and convenient to operate, mature, reliable, short in reaction route, easily available in raw materials and suitable for large-scale industrial production.
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Paragraph 0075-0079
(2021/06/23)
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- An effective reagent to functionalize alcohols with phosphocholine
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Phosphocholine is a small haptenic molecule that is both a precursor and degradation product of choline. Phosphocholine decorates a number of biologics such as lipids and oligosaccharides. In this study, an air and bench stable phosphocholine donor has been developed and evaluated with a number of alcohol acceptors. Using a one-pot, three-step sequence, (phosphitylation, oxidation, and phosphate deprotection) phosphocholine derivatives are synthesized in high yields. Of particular interest is the synthesis of miltefosine, the lone oral drug approved to treat leishmaniasis. Due to its prohibitive expense ($1500 per g), miltefosine is not accesable for the majority of the world's patients. Based on the described reaction sequence, this drug can be produced for $25 per g.
- Xu, Lianyan L.,Berg, Lawrence J.,Jamin Keith,Townsend, Steven D.
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supporting information
p. 767 - 770
(2020/02/11)
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- Total Synthesis of the Congested, Bisphosphorylated Morganella morganii Zwitterionic Trisaccharide Repeating Unit
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Zwitterionic polysaccharides (ZPSs) activate T-cell-dependent immune responses by major histocompatibility complex class II presentation. Herein, we report the first synthesis of a Morganella morganii ZPS repeating unit as an enabling tool in the synthesis of novel ZPS materials. The repeating unit incorporates a 1,2-cis-α-glycosidic bond; the problematic 1,2-trans-galactosidic bond, Gal-β-(1 → 3)-GalNAc; and phosphoglycerol and phosphocholine residues which have not been previously observed together as functional groups on the same oligosaccharide. The successful third-generation approach leverages a first in class glycosylation of a phosphoglycerol-functionalized acceptor. To install the phosphocholine unit, a highly effective phosphocholine donor was synthesized.
- Keith, D. Jamin,Townsend, Steven D.
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supporting information
p. 12939 - 12945
(2019/08/22)
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- PREPARATION OF PURIFIED PHOSPHORODIAMIDITE
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The instant invention relates to a method of phosphorodiamidite production that comprises: (E1) preparing a purified solution of a dialkylamine in a polar solvent as follows:—the dialkylamine dissolved in a polar solvent is contacted with a quantity of phosphorus trihalide that is sufficient to react with the alcohol impurities contained in the dialkylamine but sufficiently low to leave a major part of the dialkylamine unreacted, whereby a mixture is obtained that contains the dialkylamine in the polar solvent and reaction products of the impurities with the phosphorous trihalide;—the unreacted dialkylamine and polar solvent present in the mixture obtained in step (E1.1.) are extracted from the solution S by their difference of volatility, typically by distillation, whereby the purified solution of the dialkylamine in the polar solvent is obtained; (E2) the purified solution of dialkylamine in a polar solvent as obtained in step (E1) is reacted with a phosphorus trihalide, whereby an intermediate compound is formed; (E3) the intermediate compound obtained in step (E2) is reacted with a hydroxyalkyl compound in the presence of a non-polar co-solvent.
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Paragraph 0035-0038
(2016/12/01)
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- Solventless synthesis of acyl phosphonamidates, precursors to masked bisphosphonates
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A series of acyl phosphonamidates, the synthetic precursors to bisphosphonates, have been readily prepared from phosphoramidite type reagents and a range of acid chlorides. These reactions were performed using solventless conditions, where purification was easily achieved using column chromatography with yields ranging from 71-90%. Furthermore, we have demonstrated that these acyl phosphonamidates could be used for the preparation of unsymmetrical bisphosphonates, which do date are scarcely reported in the literature.
- Crossey, Kerri,Migaud, Marie E.
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supporting information
p. 11088 - 11091
(2015/07/07)
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- 2′-O-lysylaminohexyladenosine modified oligonucleotides
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Development of therapeutically active oligonucleotides for sequence-specific gene knockdown relies on chemical modifications that confer high stability and target affinity and ideally enable cellular uptake. 2′-O-Lysylaminohexyluridine-containing antisense and siRNA oligonucleotides have been shown to be well suited for gene knockdown. They are highly resistant to enzymatic degradation while having good affinity for the targeted RNA strand and efficiently down-regulate their target in cell culture tumor models. The 2′-O-lysylaminohexyl modification was expanded to adenosine nucleosides. The corresponding phosphoramidite building block was prepared in a straightforward procedure comprising six steps starting from adenosine. After 2′-O-alkylation with N-(6-bromohexyl)phthalimide and removal of the N-protecting group, the protected lysine was specifically attached to the alkylamino group. Incorporation of 2′-O- lysylaminohexyladenosine nucleotides in a test sequence confirmed that the cationic chains lead only to minor duplex destabilization and do not disturb the duplex structure. Results further emphasize the advantageous properties of 2′-O-lysylaminohexyl modified oligonucleotides for therapeutic applications. Springer-Verlag 2010.
- Winkler, Johannes,Giessrigl, Benedikt,Novak, Clemens,Urban, Ernst,Noe, Christian R.
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experimental part
p. 809 - 815
(2011/07/08)
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- Synthesis of cyclic di-nucleotidic acids as potential inhibitors targeting diguanylate cyclase
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Five analogs of cyclic di-nucleotidic acid including c-di-GMP were synthesized and evaluated for their biological activities on Slr1143, a diguanylate cyclase of Synechocystis sp. Slr1143 was overexpressed from the recombinant plasmid which contained the gene of interest and subsequently purified by affinity chromatography. A new HPLC method capable of separating the compound and product peaks with good resolution was optimized and applied to the analysis of the compounds. Results obtained show that cyclic di-inosinylic acid 1b demonstrates a stronger inhibition on Slr1143 than c-di-GMP and is a potential inhibitor for biofilm formation.
- Ching, Shi Min,Tan, Wan Jun,Chua, Kim Lee,Lam, Yulin
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scheme or table
p. 6657 - 6665
(2010/10/21)
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- PROCESS FOR PREPARING PHOSPHORODIAMIDITES
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A method of phosphorodiamidite production comprising the steps of reacting a phosphorus trihalide with a dialkyl amine in a polar solvent to form an intermediate compound. This intermediate compound is then subsequently reacted with an hydroxyalkyl compound and a dialkyl amine in the presence of a non-polar co-solvent. Following filtration to remove the solid by-product the two solvents form separate layers. This is advantageous as the upper, non-polar solvent, layer contains the high-purity phosphorodiamidite product.
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- PROCESS FOR THE PREPARATION OF PHOSPHITYLATION AGENTS
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A process for the preparation of a compound of formula R1-Y1-P(NR2R3 )2 is provided. The process comprises reacting a compound of formula PX3 with a compound of formula HNR2R3 to form a compound of formula X-P(NR2R3)2; and reacting the compound of formula X-P(NR2R3)2 with a compound of formula R1-Y1-H in the presence of a hydrocarbon solvent to form the compound of formula R1-Y1-P(NR2R3 )2. R1 represents a phosphorus protecting group; R2 and R3 each independently represent an alkyl, preferably a C1-6alkyl, group, or R2 and R3 are joined, together with the N to which they are attached, to form a 5-7 membered ring; Y1 represents O or S, preferably O; and X represents a halogen, preferably Cl. The preferred solvent is toluene.
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- PROCESS OF MAKING PHOSPHORDIAMIDITE COMPOUNDS
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A process of producing cynoalkyl tetraalkylphosphordiamidites at least substantially free of amine hydrohalide with improved storage stability.
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- Process for manufacturing purified phosphorodiamidite
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A scalable process for purification of phosphorodiamidite includes steps of solubilizing a crude phosphorodiamidite in an apolar organic solvent, contacting the non-polar organic solvent with a polar phase comprising a polar organic solvent to remove impurities from the solubilized phosphorodiamidite, and removing the non-polar organic solvent from the phosphorodiamidite.
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- Multidentate phosphite ligands, catalytic compositions containing such ligands and catalytic processes utilizing such catalytic compositions
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Hydrocyanation reactions employing multidentate phosphite ligands and multidentate phosphite ligands are disclosed. The ligands have phenyl containing substituents attached to the ortho position of the terminal phenol group and/or attached to the ortho position of the bridging group. Catalyst compositions havng such ligands achieve 97% or greater distribution in hydrocyanation.
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- 2',5'-phosphorothioate/phosphodiester oligoadenylates and anti-viral uses thereof
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Optically active antiviral compounds having the formula STR1 wherein m is 0, 1, 2, or 3; n and q are selected from the group of 0 and 1, provided that n and q may not both be zero; and R, R1, and R2 are independently of each other selected from the group consisting of oxygen and sulfur, provided that all R, R1 and R2, may not be oxygen, and further provided that all R, R1, and R2 may not be sulfur. The compounds possess increased antiviral activity and/or metabolic stability.
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- Cyclic bis-phosphites
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This invention concerns certain novel bis-cyclic phosphite compounds and polymeric materials stabilized therewith. In a preferred embodiment, this invention concerns certain cyclic bis-phosphites, derived from, for example, 4,4'-6,6'-tetra-tert-butyl-2,2'-biphenol or 2,2'-methylene-bis-(4,6-di-tert-butylphenol) as well as homologues thereof, and the corresponding chlorophosphite derivative of 1,3-glycol, and polymeric materials stabilized against thermally-induced oxidative degradation by the presence therein of at least one of the cyclic bis-phosphites.
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- Synthesis of phosphotriester analogues of the phosphoinositides PtdIns(4,5)P2 and PtdIns(3,4,5)P3
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A synthetic route was developed for the preparation of novel O-(3-aminopropyl) tethered phosphotriester analogs (5) of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5,)P2, or PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3, or PIP3) using the coupling reagent 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite. The phosphotriester ligand design introduced a reactive aminopropyl group at the polar lipid head of the ring-phosphorylated phosphoinositides, allowing a reporter moiety to be positioned at the surface of the bilayer and in the vicinity of the phosphorylated inositol. Such reporter groups may interact with membrane-proximal regions of PIP2- and PIP3-binding proteins recruited to membrane sites by electrostatic interactions between the phosphates of the phospholipid and basic regions of the proteins. Following a convergent strategy, phosphitylation of an optically-pure 1,2-O-diacyl-sn-glycerol with 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite was followed by coupling with protected inositol precursors to give adducts 8 in 80% to 95% yield. The 2-cyanoethyl phosphotriester was stable during the subsequent reaction steps and could be conveniently converted to the 3-aminopropyl group during the final hydrogenolysis of the benzyl protecting groups. Benzophenone-containing photoaffinity probes of the phosphotriester 11a and 11b were also synthesized. Alternatively, the versatile cyanoethyl group could be removed using diisopropylethylamine prior to hydrogenolysis, thereby furnishing the corresponding phosphodiesters, PIP3 and PIP2 (13a and 13b).
- Gu, Qu-Ming,Prestwich, Glenn D.
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p. 8642 - 8647
(2007/10/03)
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- 6-O-substituted guanosine derivatives
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The following species of N6-activated guanosine derivatives are disclosed: 2-N-trifluoroacetamido-6-(4-nitrophenoxy)-9-(2-deoxy-beta-D-erythro-pentofuranosyl)purine 2-N-trifluoroacetamido-6-pentafluorophenoxy-9-(2-deoxy-beta-D-erythro-pentofuranosyl)purine 6-dimethylpyridinium-9-(2-deoxy-beta-D-erythropentofuranosyl)purine These guanosine compounds are useful as precursors in the synthesis of a wide variety of antiviral and anticancer nucleosides such as 2-amino-2-deoxyadenosine or 6-thio-deoxyguanosine. Also disclosed are oligonucleotides containing the above nucleosides which are precursors to modified oligonucleotides which are useful as hybridization probes.
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- Hydrogenation of aromatic-substituted olefins using organometallic catalyst
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A ruthenium-phosphite complex having the formula STR1 wherein a is from 1 to 3; b is 1 or 2; c is from 0 to 3; and R is hydrogen, alkyl, aryl, halo, amino, acetylamino, or sulfo; and X is STR2 where R1, R2, and R3 are the same or different and are hydrogen or C1 to C6 linear or branched alkyl. This complex can be used to effect the reduction of unsaturated organic compounds or, when comprised of ligands having optical activity, can be used as the catalyst for effecting the asymmetric reduction of unsaturated organic compounds.
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- A Simple and Effective Chemical Phosphorylation Procedure for Biomolecules
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A general chemical phosphorylation method based on P(III) chemistry has been developed.The system is demonstrated for the phosphorylation of oligonucleotides, directly after their synthesis on a solid support, and for the O-phosphorylation of serine, threonine, and tyrosine as well as for a serine-containing peptide.
- Bannwarth, Willi,Trzeciak, Arnold
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p. 175 - 186
(2007/10/02)
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- New Approach to the Synthesis of Deoxyribonucleoside Phosphoramidite Derivatives
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The deoxyribonucleoside phosphoramidites with various protecting groups at phosphorus have been prepared rapidly in good yields in one-pot reaction from bis(diisopropylamino)chlorophosphine as a new phosphitylating agent without isolation of bis(diisopropylamino)alkoxyphosphines.
- Hamamoto, Shoji,Takaku, Hiroshi
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p. 1401 - 1404
(2007/10/02)
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