- Identification of fonofos metabolites in Latuca sativa, Beta vulgaris, and Triticum aestivum by packed capillary flow fast atom bombardment tandem mass spectrometry.
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The metabolism of fonofos, a thiophosphonate insecticide, was investigated in mature lettuce (Latuca sativa), beet (Beta vulgaris), and wheat (Triticum aestivum). Six new metabolites were identified by LC-MS and LC-MS-MS analysis using fast atom bombardment (FAB) and packed capillary LC columns with application of the on-column focusing technique. These methods provided the sensitivity required to identify unknown metabolites that were present in the mature plants at only 20-230 ppb. Structural elucidation was facilitated by use of fonofos labeled with both carbon-14 and carbon-13 in the phenyl ring. In all three plants fonofos was converted to a glucose conjugate of thiophenoxylactic acid. Oxidation of the glucose conjugate gave isomeric sulfoxides in all species examined. Thiophenoxylactic acid was found esterified to malonic acid in lettuce. In beets, S-phenylcysteine was found as its malonic acid amide. A second metabolite unique to beets was N-(malonyl)-[2[(ethoxyethylphosphinothionyl)oxy]phenyl]cysteine. This novel structure was confirmed by synthesis.
- Onisko, Bruce C,Tambling, Doug R,Gorder, Greg W,Diaz, David G,Ericson, John L,Prisbylla, Mike P,Spillner, Chuck J
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Read Online
- Method for synthesizing benserazide hydrochloride by utilizing fixed bed hydrogenation equipment
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The invention discloses a method for synthesizing benserazide hydrochloride by using fixed bed hydrogenation equipment, which is characterized in that a compound 1 reacts with an amino protective agent to carry out an amino protection reaction, so that the subsequent purification is easy, and the dosage of hydrazine hydrate in the synthesis method is small; according to the method, fixed bed hydrogenation equipment is used for synthesis, a fixed bed reactor is filled with a solid catalyst or a solid to realize a heterogeneous reaction process, the catalyst in the fixed bed reactor is relatively fixed, a reaction liquid flows through a bed layer, and the reaction liquid flows through the bed layer by adjusting the flow rate and the reaction pressure; qualified products can be obtained after reaction liquid flows out of the fixed bed, continuous production can be achieved, product deterioration caused by long-time contact of the products and the catalyst can be avoided, the same amount of products can be produced due to continuous production, the reactor size can be very small, the safety problem caused by high-pressure reaction is greatly reduced, the amount of the catalyst used in the reaction is less, and the production cost is reduced.
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Paragraph 0028; 0032-0033
(2021/06/02)
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- Discovery of 3-Quinazolin-4(3 H)-on-3-yl-2, N-dimethylpropanamides as Orally Active and Selective PI3Kα Inhibitors
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Phosphoinositide 3-kinases (PI3Ks) mediate a series of events related to cell growth, proliferation, survival, and differentiation. Overexpression of PI3Ks can lead to the dysregulation of cell homeostasis and cause tumorigenesis. In this study, rationally designed compounds were investigated as PI3Kα-selective inhibitors. Our efforts culminated in the discovery of a series of quinazolin-4(3H)-one derivatives with 2-substituted-N-methylpropanamide substitutions as PI3Kα-selective inhibitors. The best compound, 10, has PI3Kα enzymatic and cellular IC50 values of 1.8 and 12.1 nM, respectively. It exhibits biochemical selectivities for PI3Kα over PI3Kβ/δ/γof 150/7.72/7.67-fold and cellular selectivities of 115/15.1/>826-fold, respectively. Compound 10 is 59% orally bioavailable with a dose-normalized AUC of 3090 nM. These effects translated into in vivo conditions, as 10 significantly time- and dose-dependently inhibited phosphorylation of Akt in BT-474 subcutaneous xenograft mice and inhibited tumor growth.
- Dong, Jiaqiang,Huang, Jingjie,Zhou, Ji,Tan, Ye,Jin, Jing,Tan, Xi,Wang, Bei,Yu, Tao,Wu, Chengde,Chen, Shuhui,Wang, Tie-Lin
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supporting information
p. 1463 - 1469
(2020/08/14)
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- Quinazolinone Compound and Application Thereof
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The present invention relates to a series of quinazolinone compounds and applications thereof as PI3Kα inhibitors. In particular, the present invention relates to a compound shown in formula (I) and a tautomer or pharmaceutically acceptable salt thereof.
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Paragraph 0321-0323
(2020/11/27)
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- Synthesis method of benserazide hydrochloride
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The invention relates to a synthesis method of benserazide hydrochloride. According to the synthesis method, serine methyl ester hydrochloride is taken as the primary raw material, at first, amino protection reactions are carried out; and then amine-ester exchange reactions, condensation reactions, reduction reactions, and de-protection reactions are performed to obtain high purity benserazide hydrochloride. The synthesis method has the advantages that the raw materials are cheap and easily available, the operation is convenient, the product purity and yield of each step are high, and thus thesynthesis method is suitable for industrial production.
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Paragraph 0126- 0129
(2019/12/11)
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- Improved synthetic routes to the selenocysteine derivatives useful for Boc-based peptide synthesis with benzylic protection on the selenium atom
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Selenocysteine (Sec) derivatives, i.e., Boc-Sec(MBn)-OH (1) and Boc-Sec(MPM)-OH (2), which are useful for chemical synthesis of selenopeptides, were obtained from L-serine in five steps with total yields of 73% and 74%, respectively. The enantiomeric excesses were confirmed to be >99% e.e. by optical resolution using a chiral column on HPLC. On the other hand, for the case of a Fmoc-protected Sec derivative, i.e., Fmoc-Sec(MPM)-OH, similar reactions resulted in low yields and partial racemization taking place. [PRESENTED EQUATION]
- Shimodaira, Shingo,Iwaoka, Michio
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p. 260 - 271
(2017/03/09)
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- Efficient Synthesis of N-Sulfonyl β -Arylmethylalaninates from Serine via Ring Opening of N-Sulfonyl Aziridine-2-carboxylate
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We report the efficient synthesis of N-sulfonyl β-arylalanines methyl ester through regioselective ring opening of N-protected aziridines by variety of heteroaryl C-nucleophiles. We have optimized synthesis of N-protected aziridines with versatile protecting groups to afford 4a-c, 6a, and 6b with moderate to good yields using sulfuryl chloride, triethyl amine, and toluene at -50 °C. The present work reports on the studies related to electronic effect of nitrogen substituent on aziridination from the inexpensive starting material DL-serine. The present investigation also reports the efficient synthesis of N-sulfonyl β-arylmethylalaninates (7a-e and 8a-e) by regioselective nucleophilic ring opening of N-sulfonamido-protected aziridines using various aryl moieties such as C-nucleophiles and Lewis acids (InCl3, FeCl3, Cu(OTf)2) as catalysts and some trials by ring opening using Grignard reagent. GRAPHICAL ABSTRACT.
- Chaudhari, Prashant,Bari, Sanjay
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supporting information
p. 401 - 412
(2015/10/29)
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- 1,3,4-OXADIAZOLE AND 1,3,4-THIADIAZOLE BETA-LACTAMASE INHIBITORS
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β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.
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Page/Page column 108; 109
(2013/10/21)
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- One-pot synthesis of α-amino acids from CO2 using a bismetal reagent with Si-B bond
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In the presence of 1.1 equiv of PhMe2Si-Bpin, 5 equiv of CsF, and 20 mol % of TsOH·H2O, precursors of N-Boc-imines can be converted into the corresponding α-aryl or α-alkenyl glycine derivatives under gaseous CO2 in moderate-to-high yields with a single operation. α-Isobutenyl glycine thus obtained can be further derivatized into various types of α-amino acids including N-Boc-leucine, serine, and glycine derivatives in short steps.
- Mita, Tsuyoshi,Chen, Jianyang,Sugawara, Masumi,Sato, Yoshihiro
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p. 6202 - 6205
(2013/02/23)
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- Fluorinated cyclopropane analogs of glutamic acid
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The present invention relates to a compound of the following formula (I): or a pharmaceutically acceptable salt, a stereoisomer or a mixture in all proportions of stereoisomers thereof, in particular a mixture of enantiomers, such as a racemic mixture, wh
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Page/Page column 13
(2011/02/25)
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- FLUORINATED CYCLOPROPANE ANALOGS OF GLUTAMIC ACID
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The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, a stereoisomer or a mixture in all proportions of stereoisomers thereof, in particular a mixture of enantiomers, such as a racemic mixture, wherein R represents a (C1-C6)alkyl or (C1-C6)alkenyl group, optionally substituted by one or more groups chosen among an halogen atom, ORa, SRb, NRcRd, PO(ORe)(ORf), CO2Rg, SO2Rh SO3R1, P0(0H)(CH(0H)Rk), CN, N3 and NH- C(=NH)NH2, with Ra, Rb, Rc and Rd, representing, independently of each other, an hydrogen atom, a (C1-C6)alkyl group or a -CO-(C1-C6)alkyl group, Re, Rf, Rg, Rh and R1 representing, independently of each other, an hydrogen atom or a (C1-C6)alkyl group, and Rk representing an aryl or heteroaryl group, said group being optionally substituted by one or more groups selected from an halogen atom and NO2, as well as to the use thereof and to a process for preparing such a compound, to a pharmaceutical composition containing it and to synthesis intermediates.
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Page/Page column 19; 20
(2011/02/24)
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- Access to enantioenriched α-amino esters via rhodium-catalyzed 1,4-addition/enantioselective protonation
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Conjugate addition of potassium trifluoro(organo)borates 2 to dehydroalanine derivatives 1, mediated by a chiral rhodium catalyst and in situ enantioselective protonation, afforded straightforward access to a variety of protected α-amino esters 3 with high yields and enantiomeric excesses up to 95%. Among the tested chiral ligands and proton sources, Binap, in combination with guaiacol (2-methoxyphenol), an inexpensive and nontoxic phenol, afforded the highest asymmetric inductions. Organostannanes have also shown to participate in this reaction. By a fine-tuning of the ester moiety, and using Difluorophos as chiral ligand, increased levels of enantioselectivity, generally close to 95%, were achieved. Deuterium labeling experiments revealed, and DFT calculation supported, an unusual mechanism involving a hydride transfer from the amido substituent to the α carbon explaining the high levels of enantioselectivity attained in controlling this α chiral center.
- Navarre, Laure,Martinez, Remi,Genet, Jean-Pierre,Darses, Sylvain
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p. 6159 - 6169
(2008/12/20)
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- A new family of small molecules to probe the reactivation of mutant p53
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Cells that express mutant p53 derived from cancers are selectively killed by a new class of small organic molecules. The protein p53 is recognized as one of the most important guardians in the body that prevents tumor development. Mutant forms of p53 are
- Myers, Michael C.,Wang, JinLing,Iera, Jaclyn A.,Bang, Jeong-Kyu,Saito, Shin'ichi,Hara, Toshiaki,Zambetti, Gerard P.,Appella, Daniel H.
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p. 6152 - 6153
(2007/10/03)
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- COMPOUNDS AND RELATED METHODS FOR MUTANT p53 REACTIVATION
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Ketoamine compounds and related methods for reactivation of tumor suppressor protein p53.
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Page/Page column 34
(2008/06/13)
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- A solid-phase approach to DDB derivatives
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Since the discovery of 2,2′-dimethoxycarbonyl-4,4-dimethoxy-5,6, 5′,6′-biomethylenedioxy-biphenyl (DDB) as a potent anti-HBV agent, we have studied the structure-activity relationships of 4,4′-dimethoxy-5, 6,5′,6′-dimethenedioxy-2-alkyloxycarbonyl-2′-(4-substituted benzyl piperazin-1-yl)carbonyl-biphenyl as anti-HBV agents. Therefore, it is rational to extend this study to the 3,3′-disustituted-4,4′- dimethoxy-5,6,5′,6′-dimethenedioxy-2-alkyloxycarbonyl-2′- Serine derivatives. Thus, in an attempt to develop an efficient method for the preparation of a large number of DDB derivatives, the reaction between a DDB acid chloride and serine derivatives on solid support was studied. The structure of resulted compounds was confirmed by LC-MS and 1H NMR analysis. Compounds 2a, 2d, 2f, 2j showed in vitro anti-HBV activity without significant toxicity up to 100 μM.
- Qi, Xiuxiang,Wang, Xiaolai,Wang, Limin,Wang, Qiang,Cheng, Senxiang,Suo, Jishuan,Chang, Junbiao
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p. 805 - 810
(2007/10/03)
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- Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease
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Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn2+-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn2+ conditions (Ki=27 nM). This compound (46) binds also to NS3/NS4A in a Zn2+ independent fashion (Ki=1 μM). The SAR of this class of compounds under Zn2+ conditions is highly divergent compared to the SAR in the absence of Zn2+, suggesting two distinct binding modes.
- Sperandio, David,Gangloff, Anthony R.,Litvak, Joane,Goldsmith, Richard,Hataye, Jason M.,Wang, Vivian R.,Shelton, Emma J.,Elrod, Kyle,Janc, James W.,Clark, James M.,Rice, Ken,Weinheimer, Steve,Yeung, Kap-Sun,Meanwell, Nicholas A.,Hernandez, Dennis,Staab, Andrew J.,Venables, Brian L.,Spencer, Jeffrey R.
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p. 3129 - 3133
(2007/10/03)
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- A facile and chemoselective cleavage of trityl ethers by indium tribromide
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Trityl ethers are chemoselectively, deprotected to the corresponding alcohols in high yields by a catalytic amount of indium tribromide in aqueous acetonitrile. The method is compatible with various functional groups such as acetonides, acetates, benzoates, olefins, carbamates, esters and ethers present in the substrate.
- Yadav,Reddy, B.V. Subba,Srinivas,Maiti
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p. 528 - 529
(2007/10/03)
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- Di-tert-butyl dicarbonate and 4-(dimethylamino)pyridine revisited. Their reactions with amines and alcohols
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The reaction of BOC2O in the presence and absence of DMAP was examined with some amines, alcohols, diols, amino alcohols, and aminothiols. Often, unusual products were observed depending on the ratio of reagents, reaction time, polarity of solvent, pK(a) of alcohols, or type of amine (primary or secondary). In reactions of aliphatic alcohols with BOC2O/DMAP, we isolated for the first time carbonic-carbonic anhydride intermediates; this helps explain the formation of symmetrical carbonates in addition to the O-BOC products. In the case of secondary amines, we succeeded to isolate unstable carbamic-carbonic anhydride intermediates that in the presence of DMAP led to the final N-BOC product. The effect of N-methylimidazole in place of DMAP was also examined.
- Basel, Yochai,Hassner, Alfred
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p. 6368 - 6380
(2007/10/03)
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- A mild and selective cleavage of tert-butyldimethylsilyl ethers by indium(III) chloride
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Alkyl tert-butyldimethylsilyl ethers are selectively deprotected to the corresponding alcohols in high yields for the first time by indium(III) chloride in refiuxing aqueous acetonitrile. Several functional groups like OBn, Boc, CBz, OBz, O-allyl, OTBDPS, OAc, OMe, ethers, esters and olefins present in the substrate are unaffected.
- Yadav,Subba Reddy,Madan
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p. 853 - 854
(2007/10/03)
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- Efficient tin hydride-mediated radical cyclisation of secondary amides leading to substituted pyrrolidinones. Part 2. Application to the synthesis of aromatic kainic acid analogues
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An enantioselective synthesis of phenyl allokainoid, starting from D-serine, is reported. Tin-mediated cyclisation of a secondary amide was used in the key step to produce a trisubstituted pyrrolidinone in excellent yield (ca. 80%). The predominant format
- Bryans, Justin S.,Large, Jonathan M.,Parsons, Andrew F.
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p. 2905 - 2910
(2007/10/03)
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- Cross-metathesis of unsaturated α-amino acid derivatives
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Cross-metathesis of homoallylglycine derivatives with aryl- and alkyl-substituted alkenes using the ruthenium catalyst (Cy3P)2Cl2Ru=CHPh 1 has been achieved in 43-55 and 55-66% yield respectively. Allylglycine, vinylglycine and dehydroalanine derivatives have also been examined. Whilst cross-metathesis of allylglycine derivatives with alkyl-substituted alkenes using catalyst 1 may be regarded as a synthetically useful procedure, cross-metathesis reactions of vinylglycine and dehydroalanine derivatives using catalyst 1 are non-viable. Attachment of FmocHagOH 13 to a capped Wang resin, cross-metathesis with dodec-1-ene, and product removal from the resin gives the cross-metathesis product in 74% yield based on FmocHagOH.
- Biagini, Stefano C. G.,Gibson, Susan E.,Keen, Stephen P.
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p. 2485 - 2499
(2007/10/03)
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- Synthese d'aminoacides cyclopropaniques par reaction du diazoacetate d'ethyle sur des methyleneglycinates N-proteges
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We report a synthesis of glutamic acid analogs, 1-aminocyclopropan-1,2-dicarboxylic acid derivatives, by reaction of ethyl diazoacetate with N-protected methylene glycinates in the presence of achiral and chiral copper complexes.The cyclopropanation is effective with these catalysts but the Pfaltz chiral complex did not induce any enantioselectivity.
- Abdioui, Khalid L.,Martinez, Jean,Viallefont, Philippe,Vidal, Yves
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p. 425 - 432
(2007/10/03)
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- MILD AND SELECTIVE RING-CLEAVAGE OF CYCLIC CARBAMATES TO AMINO ALCOHOLS
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N-tert-Butoxycarbonylated 2-oxazolidinones and tetrahydro-2-oxazinones are smoothly cleaved to acyclic N-Boc-amino alcohols on treatment with catalytic amounts of cesium carbonate at room temperature.The versatility of the procedure is demonstrated in a facile cleavage of highly functionalized heterocycles without epimerization and β-elimination.
- Ishizuka, Tadao,Kunieda, Takehisa
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p. 4185 - 4188
(2007/10/02)
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