- Characterization of novel glutathione adducts of a non-nucleoside reverse transcriptase inhibitor, (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihyd ro-2(1h)-quinazolinone (DPC 961), in rats. Possible formation of an oxirene metabolic intermediate from a disubstituted alkyne
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The postulated formation of oxirene-derived metabolites from rats treated with a disubstituted alkyne, (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3-4-dihyd ro-2(1H)-quinazolinone (DPC 961), is described. The reactivity of this postulated oxirene intermediate led to the formation of novel glutathione adducts whose structures were confirmed by LC/MS and by two-dimensional NMR experiments. These metabolites were either excreted in rat bile or degraded to mercapturic acid conjugates and eliminated in urine. To demonstrate the oxidation of the triple bond, an analogue of DPC 961 was synthesized, whereby the two carbons of the alkyne moiety were replaced with 13C stable isotope labels. Rats were orally administered [13C]DPC 961 and glutathione adducts isolated from bile. The presence of an oxygen atom on one of the 13C labels of the alkyne was demonstrated unequivocally by NMR experiments. Administration of 14C-labeled DPC 961 showed that biliary elimination was the major route of excretion with the 8-OH glucuronide conjugate (M1) accounting for greater than 90% of the eliminated radioactivity. On the basis of radiochemical profiling, the glutathione-derived metabolites were minor in comparison to the glucuronide conjugate. Studies with cDNA-expressed rat enzymes, polyclonal antibodies, and chemical inhibitors pointed to the involvement of P450 3A1 and P450 1A2 in the formation of the postulated oxirene intermediate. The proposed mechanism shown in Scheme i begins with P450-catalyzed formation of an oxirene, rearrangement to a reactive cyclobutenyl ketone, and a 1,4-Michael addition with endogenous glutathione to produce two isomeric adducts, GS-1 and GS-2. The glutathione adducts were subsequently catabolized via the mercapturic acid pathway to cysteinylglycine, cysteine, and N-acetylcysteine adducts. The transient existence of the α,β-unsaturated cyclobutenyl ketone was demonstrated by incubating the glutathione adduct in the presence of N-acetylcysteine and monitoring the formation of N-acetylcysteine adducts by LC/MS. Epimerization of GS-1 to GS-2 was also observed when N-acetylcysteine was omitted from the incubation.
- Mutlib,Chen,Shockcor,Espina,Chen,Cao,Du,Nemeth,Prakash,Gan
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Read Online
- Thiourea-Mediated Halogenation of Alcohols
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The halogenation of alcohols under mild conditions expedited by the presence of substoichiometric amounts of thiourea additives is presented. The amount of thiourea added dictates the pathway of the reaction, which may diverge from the desired halogenation reaction toward oxidation of the alcohol, in the absence of thiourea, or toward starting material recovery when excess thiourea is used. Both bromination and chlorination were highly efficient for primary, secondary, tertiary, and benzyl alcohols and tolerate a broad range of functional groups. Detailed electron paramagnetic resonance (EPR) studies, isotopic labeling, and other control experiments suggest a radical-based mechanism. The fact that the reaction is carried out at ambient conditions, uses ubiquitous and inexpensive reagents, boasts a wide scope, and can be made highly atom economic, makes this new methodology a very appealing option for this archetypical organic reaction.
- Mohite, Amar R.,Phatake, Ravindra S.,Dubey, Pooja,Agbaria, Mohamed,Shames, Alexander I.,Lemcoff, N. Gabriel,Reany, Ofer
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p. 12901 - 12911
(2020/11/26)
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- Palladium-Catalyzed Cascade Intramolecular Cyclization and Allylation of Enynoates with Allylic Alcohols
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A Pd(II)-catalyzed mild and highly regioselective 6-endo cyclization/allylation reaction of enynoates with simple allylic alcohols has been developed. Under mild reaction conditions, the vinyl palladium species generated in situ after cyclization could insert C-C double bond of allylic alcohol through cross-coupling reaction and lead to the formation of allyl pyrone via β-OH elimination. This cascade cross-coupling reaction represents a direct and atom economic methodology for the construction of novel allyl pyrones in moderate to good yields.
- Qiu, Sheng-Qi,Ahmad, Tanveer,Xu, Yun-He,Loh, Teck-Peng
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p. 6729 - 6736
(2019/06/14)
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- Continuous-Flow Multistep Synthesis of Cinnarizine, Cyclizine, and a Buclizine Derivative from Bulk Alcohols
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Cinnarizine, cyclizine, buclizine, and meclizine belong to a family of antihistamines that resemble each other in terms of a 1-diphenylmethylpiperazine moiety. We present the development of a four-step continuous process to generate the final antihistamines from bulk alcohols as the starting compounds. HCl is used to synthesize the intermediate chlorides in a short reaction time and excellent yields. This methodology offers an excellent way to synthesize intermediates to be used in drug synthesis. Inline separation allows the collection of pure products and their immediate consumption in the following steps. Overall isolated yields for cinnarizine, cyclizine, and a buclizine derivative are 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h-1. The incredible bulk: Bulk alcohols are converted continuously into chlorides using HCl in a microflow. A reaction network that consists of four steps and two inline separations leads to the continuous preparation of cinnarizine, cyclizine, and a buclizine derivative with yields of 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h-1.
- Borukhova, Svetlana,Nol, Timothy,Hessel, Volker
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- METHOD FOR PRODUCING UNSATURATED GROUP-CONTAINING HALIDE
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PROBLEM TO BE SOLVED: To provide a method for producing an unsaturated group-containing halide whereby an unsaturated group-containing halide expected or used as an intermediate in the fields of medicine, agrochemical, resin and the like can be produced by a safe method, easily and at good yields. SOLUTION: The present invention provides a method for producing an unsaturated group-containing halide represented by formula (3) by halogenating an unsaturated group-containing alcohol represented by formula (2), in the presence of an organic base, with a sulfonic acid halide as a halogenating agent [R2 and R3 are H or unsubstituted; n is an integer of 1-6; and an unsaturated bond is a double bond or a triple bond]. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0039; 0040
(2017/03/28)
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- Aromatic cation activation: Nucleophilic substitution of alcohols and carboxylic acids
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A new method for the nucleophilic substitution of alcohols and carboxylic acids using aromatic tropylium cation activation has been developed. This article reports the use of chloro tropylium chloride for the rapid generation of alkyl halides and acyl chlorides under very mild reaction conditions. It demonstrates, for the first time, the synthetic potential of tropylium cations in promoting chemical transformations.
- Nguyen, Thanh V.,Bekensir, Alp
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supporting information
p. 1720 - 1723
(2014/04/17)
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- ω-alkyne-mono- and diphosphonates - Synthesis and sonogashira cross-coupling reaction with aryl halides
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A convergent approach to functionalise aromatic compounds with a linker terminated by a phosphonate group is reported. The starting point of this strategy is the synthesis of five new ω-alkyne-phosphonates. The linker between the phosphonate group and the alkyne part is either an alkyl or an ether chain. This strategy is based on the use of the phosphonate group as the anchoring point for the attachment of organic compounds onto alumina and the alkyne group, which is used to functionalise aryl halide compounds by a Sonogashira cross-coupling. The use of 1,10-phenanthroline as substrate illustrates the application of this strategy to an aromatic ligand. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Delain-Bioton, Lise,Villemin, Didier,Jaffres, Paul-Alain
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p. 1274 - 1286
(2008/09/18)
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- Preparation of cycloalkylacetylene compounds using dialkylaminomagnesium halide or bis(dialkylamino)magnesium
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The process of invention reacts an alkynyl halide with a mixture that includes a dialkylaminomagnesium halide or a bis(dialkylamino)magnesium compound to produce a cycloalkylacetylene compound. Preferably, the dialkylaminomagnesium halide compound is of the general formula R 2 NMgX (where R is a linear, branched, or cyclic alkyl substituent or R 2 N represents a heterocyclic alkyl amine and X is Cl, Br, or I) and the bis(dialkylamino)magnesium compound is of the general formula (R 2 N) 2 Mg (where R is a linear, branched, or cyclic alkyl substituent or R 2 N represents a heterocyclic alkylamine). In a preferred method of the invention, the reaction is conducted at moderate temperatures for a period of about 12 to 24 hours. The reaction mixture preferably includes tetrahydrofuran (THF), or a hydrocarbon, or a hydrocarbonether mixture. The preferred compounds produced by this process are cycloalkylacetylene compounds having 5 to 20 carbons, such as cyclopropylacetylene and cyclobutylacetylene.
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- Enhancement of through-space and through-bond π-orbital interactions. Syntheses and properties of permethylated and perspirocyclopropanated cyclotetradeca-1,3,6,9,12-pentayne
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The permethylated and perspirocyclopropanated cyclotetradeca-1,3,6,9,12-pentaynes 1 and 2 have been synthesized and completely characterized by 1H NMR, 13C NMR, UV, IR, and mass spectroscopy, as well as by X-ray crystal structure analysis. In the permethylated pentayne, compression of the internal C-C-C bond angles at the saturated carbon atoms flanking the diyne (103.8°) enhances the through-space π-orbital interactions and causes a bathochromic shift in the long wavelength UV absorption maximum (λmax 266 nm) relative to that of reference compounds (λmax 255-259 nm). In the perspirocyclopropanated pentayne, wider internal C-C-C bond angles at the corresponding carbon atoms (109.2°) reduce the through-space π-orbital interactions, but the through-bond π-orbital interactions are enhanced by spirocyclopropanation and cause a shift in the long wavelength UV absorption maximum to even longer wavelength (λmax 273 nm).
- Scott, Lawrence T.,Cooney, Mark J.,Otte, Carola,Puls, Carsten,Haumann, Thomas,Boese, Roland,Carroll, Patrick J.,Smith III, Amos B.,De Meijere, Armin
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p. 10275 - 10283
(2007/10/02)
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- Versatile syntheses of alkynyl- and substituted alkynylcyclopropanes: 2-Alkoxyethynylcyclopropanes for the anellation of bicyclo[3.3.0]octane fragments
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Enol ethers 1a-f are brominated at -78°C and the resulting alkyl 1,2-dibromoethyl ethers are regioselectively coupled with propargylmagnesium bromide to give 4-alkoxy-5-bromo-1-pentynes 2a-f, which are protected at the acetylenic terminus with a trimethylsilyl group. These 4-alkoxy-5-bromo-1-trimethylsilyl-1-pentynes 3a-f readily cyclize by γ-elimination to give trimethylsilyl protected 2-alkoxyethynylcyclopropanes 4a-f in excellent overall yields. Under appropriate conditions (E)-diastereomers (E)-4a-f can be prepared selectively. The diastereoselectivity of the bromine addition onto enantiomerically pure chiral enol ethers 1e and 1f, however, is 64% (for 2f) at best. 2-Alkoxy-1-trimethylsilylethynylcyclopropanes(E/Z)-4 can be deprotonated with LDA or butyllithium to give configurationally stable 1-lithio derivatives (E)-6, which are trapped by reactive electrophiles (protons, carbonyl compounds, tosyl halides) with retention of configuration on the three-membered ring. 2-Alkoxy-1-ethynylcyclopropanes 5 can be used to anellate a bicyclo[3.3.0]octane fragment onto a cycloalkene in a domino-type reaction sequence, as demonstrated by the Pauson-Khand cycloaddition of(E)-5c to norbornene (14) as well as deltacyclene (20), and subsequent interconversion to the tetracyclic and hexacyclic compounds anti/syn-19 and anti/syn-25/27 with a reasonable degree of diastereoselectivity.
- Militzer,Schomenauer,Otte,Puls,Hain,Brase,De Meijere
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p. 998 - 1012
(2007/10/02)
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