- Preparation methods of tenofovir alafenamide fumarate isomer impurities
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The invention discloses preparation methods of tenofovir alafenamide fumarate isomer impurities, which comprise preparation methods of four isomer impurities, specifically, preparation methods of 9-{(R)-2-[((R)-{[(R)-1-(isopropoxycarbonyl) ethyl] amino}-phenoxy phosphoryl) methoxy] propyl} adenine, 9-{(R)-2-[((R)-{[(S)-1-(isopropoxycarbonyl) ethyl] amino}-phenoxy phosphoryl) methoxy] propyl} adenine, 9-{(R)-2-[((S)-{[(R)-1-(isopropoxycarbonyl) ethyl] amino}-phenoxy phosphoryl) methoxy] propyl} adenine and 9-{(S)-2-[((R)-{[(R)-1-(isopropoxycarbonyl) ethyl] amino}-phenoxy phosphoryl) methoxy] propyl} adenine. The preparation methods of tenofovir alafenamide fumarate isomer impurities have the beneficial effects that the methods are simple and easy to implement, raw materials are easy to obtain, conditions are mild, cost is low, production is facilitated, and meanwhile the obtained isomer impurity has important significance in preparing high-purity tenofovir alafenamide fumarate.
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Paragraph 0093; 0095
(2020/07/13)
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- Antiviral novel nucleoside reverse transcriptase inhibitors
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The invention relates to compounds of antiviral novel nucleoside reverse transcriptase inhibitors, pharmaceutical compositions containing the compounds, and preparation and use of the compounds, and particularly discloses fused pyrimidine compounds shown in formula (I) and the pharmaceutical compositions containing the compounds, pharmaceutically acceptable salts, stereoisomers, solvates, hydrates, crystal forms, prodrugs or isotope derivatives. The compounds can be used for treating and/or preventing viral infectious diseases, such as human immunodeficiency virus (HIV) and hepatitis B virus (HBV). The formula (I) is shown in the specification.
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Paragraph 0317; 0318; 0320; 0321; 0322
(2019/02/25)
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- Tenofovir diester compounds and salts thereof, preparation method and medicine application of compounds
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The invention discloses tenofovir diester compounds (Ia) as well as salts of the compounds, diastereoisomers (Ib) of the compounds and salts of (Ib). The invention also discloses a preparation methodand pharmaceutical composition containing the compounds. Tests prove that the compounds have activity of inhibiting HIV-1/HBV replication, and meanwhile, the compounds have the advantages of higher lipid solubility, higher bioavailability, higher activity, lower toxicity and the like than existing TDF (tenofovir disoproxil fumarate) and TAF (tenofovir alafenamide fumarate) medicines for treating AIDS. Experiments also prove that the compounds have activity of inhibiting HBV replication and can be applied to development of medicines for treating AIDS or hepatitis B.
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Paragraph 0056-0063
(2019/03/24)
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- Puerarin derivative and preparation method and application thereof
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The invention relates to a puerarin derivative and a preparation method and an application thereof. The puerarin derivative is prepared through six steps of reactions by taking puerarin and L-alanineisopropyl ester hydrochloride as main raw materials. The puerarin derivative not only has good water solubility, but also has good anti-platelet aggregation action and can be used for preparing anti-platelet aggregation drugs. In addition, the reaction conditions of the reactions for preparing the puerarin derivative are mild, and the synthetic method is simple.
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Paragraph 0066; 0067
(2019/04/06)
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- HCV POLYMERASE INHIBITORS
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The invention provides compounds of the formula:wherein B is a nucleobase selected from the groups (a) to (d):and the other variables are as defined in the claims, which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.
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Page/Page column 76; 77
(2020/02/14)
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- COMBINATION THERAPY COMPRISING TENOFOVIR ALAFENAMIDE HEMIFUMARATE AND COBICISTAT FOR USE IN THE TREATMENT OF VIRAL INFECTIONS
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The use of the hemifumarate form of {9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine} (tenofovir alafenamide hemifumarate) in combination with cobicistat is disclosed. In addition, the combination of tenofovir alafenamide hemifumarate, cobicistat, emtricitabine, and elvitegravir, and the combination of tenofovir alafenamide hemifumarate, cobicistat, emtricitabine, and darunavir, are disclosed.
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Paragraph 0296; 0297
(2017/08/01)
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- DIOXOLANE ANALOGUES OF URIDINE FOR THE TREATMENT OF CANCER
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The invention provides compounds of formula (I), wherein: R1 is OR11, or NR5R5'; R2 is H or F; R5 is H, C1-C6alkyl, OH, C(=O)R6, O(C=O)R6 or O(C=O)OR6; R5′ is H or C1-C6alkyl; R6 is C1-C6alkyl or C3-C7cycloalkyl; R13 is H, phenyl, pyridyl, benzyl, indolyl or naphthyl wherein the phenyl, pyridyl, benzyl, indolyl and naphthyl is optionally substituted with 1, 2 or 3 R22; and the other variables are as defined in the claims, which are of use in the treatment of cancer, and related aspects.
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Page/Page column 47
(2016/03/22)
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- HCV POLYMERASE INHIBITORS
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The invention provides compounds of the formula:(I) wherein B is a nucleobase selected from the groups (a) to (d) and the other variables are as defined in the claims, which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.
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Page/Page column 64
(2015/03/28)
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- HCV POLYMERASE INHIBITORS
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The invention provides compounds of the formula (I) wherein B is a nucleobase selected from the groups (a) to (d): and the other variables are as defined in the claims, which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.
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Page/Page column 66
(2015/05/05)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF TENOFOVIR ALAFENAMIDE OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention provides an improved process for the preparation of Tenofovir alafenamide or pharmaceutically acceptable salts thereof in high yield and purity. Also provided is a process for the separation of diastereomers of Tenofovir alafenamide by simulated moving bed chromatography or preparative high performance liquid chromatography.
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Page/Page column 18
(2015/04/15)
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- Efficient microwave-assisted esterification reaction employing methanesulfonic acid supported on alumina as catalyst
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A rapid and efficient protocol assisted by microwave irradiation for the synthesis of esters using methanesulfonic acid (CH3SO3H) supported on Al2O3 (AMA) as catalyst and free of solvent is described. The products were obtained in good yields and purity, with reduced reaction time, and the process is simple and environmentally benign. Copyright
- Fabian, Lucas,Gomez, Matias,Kuran, Juan A. Caturelli,Moltrasio, Graciela,Moglioni, Albertina
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p. 2386 - 2392
(2014/07/22)
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- 1H NMR study on the intermolecular interactions of macrocyclic and single α-Amino acids
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Through analysis of 1H NMR spectra, evidence was found for intermolecular interactions between macrocyclic amino acid derivatives from L-tyrosine and their importance in the formation of aggregates in solution. It was also shown that both macrocyclic and simple amino acids are capable of retaining alcohol molecules through hydrogen bonding, where the alcohol molecule acts as a proton donor and the amino group acts as an acceptor.
- Quevedo, Rodolfo,Pabón, Laura,Quevedo-Acosta, Yovanny
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- Methods for preparing anti-viral nucleotide analogs
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Methods for isolating 9-{(R)-2-[((S)-{[(S)-1-(isopropoxycarbonyl)ethyl]amino}phenoxyphosphinyl)methoxy]propyl}adenine (compound 16): a method for preparing, in high diastereomeric purity, intermediate compounds 13 and 15: and a method for preparing intermediate compound 12: 9-{(R)-2-[((S)-{[(S)-1-(isopropoxycarbonyl)ethyl]amino}phenoxyphosphinyl)methoxy]propyl}adenine has anti-viral properties.
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Paragraph 0029; 0030
(2013/04/13)
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- Comparison of liquid chromatography-isotope ratio mass spectrometry (LC/IRMS) and gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) for the determination of collagen amino acid δ13C values for palaeodietary and palaeoecological reconstruction
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Results are presented of a comparison of the amino acid (AA) δ13C values obtained by gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) and liquid chromatography-isotope ratio mass spectrometry (LC/IRMS). Although the primary focus was the compound-specific stable carbon isotope analysis of bone collagen AAs, because of its growing application for palaeodietary and palaeoecological reconstruction, the results are relevant to any field where AA δ13C values are required. We compare LC/IRMS with the most up-to-date GC/C/IRMS method using N-acetyl methyl ester (NACME) AA derivatives. This comparison involves the analysis of standard AAs and hydrolysates of archaeological human bone collagen, which have been previously investigated as N-trifluoroacetyl isopropyl esters (TFA/IP). It was observed that, although GC/C/IRMS analyses required less sample, LC/IRMS permitted the analysis of a wider range of AAs, particularly those not amenable to GC analysis (e.g. arginine). Accordingly, reconstructed bulk δ13C values based on LC/IRMS-derived δ13C values were closer to the EA/IRMS-derived δ13C values than those based on GC/C/IRMS values. The analytical errors for LC/IRMS AA δ13C values were lower than GC/C/IRMS determinations. Inconsistencies in the δ13C values of the TFA/IP derivatives compared with the NACME- and LC/IRMS-derived δ13C values suggest inherent problems with the use of TFA/IP derivatives, resulting from: (i) inefficient sample combustion, and/or (ii) differences in the intra-molecular distribution of δ13C values between AAs, which are manifested by incomplete combustion. Close similarities between the NACME AA δ13C values and the LC/IRMS-derived δ13C values suggest that the TFA/IP derivatives should be abandoned for the natural abundance determinations of AA δ13C values.
- Dunn, Philip J. H.,Honch, Noah V.,Evershed, Richard P.
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experimental part
p. 2995 - 3011
(2012/05/20)
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- Practical synthesis, separation, and stereochemical assignment of the PMPA pro-drug GS-7340
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The practical synthesis of a mixed phenoxy-amidate derivative of PMPA with high oral bioavailability and favorable pharmacokinetics is described. The non-stereoselective synthetic route produces a 1:1 mixture of two diastereomers at phosphorous. Simulated moving bed chromatography using Chiralpak AS enabled kilo-scale isolation of the more potent diastereomer (GS-7340). The GS-7340 phosphorous chiral center was found to be (S) by X-ray crystallography.
- Chapman,Kernan,Prisbe,Rohloff,Sparacino,Terhorst,Yu
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p. 621 - 628
(2007/10/03)
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- Stable Nitrogen Isotope Analysis of Amino Acid Enantiomers by Gas Chromatography/Combustion/ Isotope Ratio Mass Spectrometry
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The analysis of the stable nitrogen isotope compositions of individual amino acid stereoisomers through the use of gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) is presented. Nitrogen isotopic compositions of single amino acids or of their enantiomers is possible without the labor-intensive and time-consuming preparative-scale chromatographic procedures required for conventional stable isotope analysis. Following hydrolysis and derivatization, single-component isotope analysis is accomplished on nanomole quantities of each of the stereoisomers of an amino acid, utilizing the effluent stream of gas chromatographic separation. Nitrogen isotope fractionation is minimal during acylation of the amino acid, with no additional nitrogen being added stoichiometrically to the derivative. Thus, the isotopic composition of the nitrogen in the derivative is that of the original compound. Replicate stable nitrogen isotope analyses of 11 amino acids, and their trifluoroacetyl (TFA)/isopropyl (IP) ester derivatives, determined by both conventional isotope ratio mass spectrometry (IRMS) and GC/C/IRMS, indicate that the GC procedure is highly reproducible (standard deviations typically 0.3-0.4‰) and that isotopic differences between the amino acid and its TFA/IP derivative are, in general, less than 0.5‰.
- Macko, Stephen A.,Uhle, Maria E.,Engel, Michael H.,Andrusevich, Vladimir
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p. 926 - 929
(2007/10/03)
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- Stable carbon isotope analysis of amino acid enantiomers by conventional isotope ratio mass spectrometry and combined gas chromatography/isotope ratio mass spectrometry
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The application of a combined gas chromatography/isotope ratio mass spectrometry (GC/IRMS) method for stable carbon isotope analysis of amino acid enantiomers is presented. This method eliminates the numerous preparative steps integral to the isolation of amino acids and amino acid enantiomers from protein hydrolyzates that precede δ13C analysis by conventional isotope ratio mass spectrometry. Unlike hydrocarbons, amino acids require derivatization prior to GC/ IRMS analysis. Replicate δ13C analyses of trifluoroacetyl (TFA) isopropyl ester derivatives of 22 amino acids by IRMS revealed that the derivatization process is reproducible, with an average error (1 standard deviation) of 0.10‰ ± 0.09 ‰. The average analytical error for analysis of amino acid derivatives by GC/IRMS was 0.26‰ ± 0.09‰. In general, absolute differences between IRMS and GC/IRMS analyses were less than 0.5‰. The derivatization process introduces a distinct, reproducible isotopic fractionation that is constant for each amino acid type. The observed fractionations preclude direct calculation of underivatized amino acid δ13C values from their respective TFA isopropyl ester δ13C compositions through mass balance relationships. Derivatization of amino acid standards of known stable carbon isotope compositions in conjunction with natural samples, however, permits computation of the original, underivatized amino acid δ13C values through use of an empirical correction for the carbon introduced during the derivatization process.
- Silfer,Engel,Macko,Jumeau
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p. 370 - 374
(2007/10/02)
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- Nucleophilic Substitution Reactions of Alkyl Halides By Using New Polymer-Supported Reagents Containing Hemin
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A new polymer reagent consisting of hemin, divinylbenzene, and 2-methyl-5-vinylpyridine was synthesized by suspension copolymerization.Substitution reactions of primary, secondary, and tertiary alkyl halides with the hemin copolymer combined with cyanide, azide, and thiocyanate ions were given satisfactory yields.This reaction mechanism was revealed to be a SNi type on the basis of stereochemical study.The hemin copolymer was not only a polymer-supported reagent with functional capabilities, but also served to separate the product from the reaction mixture.
- Saito, Kiyoshi,Harada, Kaoru
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p. 2562 - 2566
(2007/10/02)
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- ENANTIOSELECTIVE HYDROLYSIS BY BAKER'S YEAST - II. ESTERS OF N-ACETYL AMINO ACIDS
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D-N-Acetyl amino acid esters were obtained via enantioselective hydrolysis of their racemates by use of fermenting yeast.Evidence is given that proteinases are the enzymes involved.
- Glaenzer, B. I.,Faber, K.,Griengl, H.
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p. 771 - 778
(2007/10/02)
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