- Scalable asymmetric synthesis of a key fragment of Bcl-2/Bcl-xLinhibitors
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The asymmetric synthesis of a 1,3-diamine building block for the elaboration of Bcl-2 and Bcl-xLprotein inhibitors is described through two key steps: (1) a highly diastereoselective aza-Reformatsky reaction, and (2) a chemoselective amination under Mitsunobu conditions. This synthetic sequence was also demonstrated to be successfully amenable to a large-scale synthesis. This journal is
- Laclef, Sylvain,Taillier, Catherine,Penloup, Christine,Viger, Aurélie,Brière, Jean-Fran?ois,Hardouin, Christophe,Levacher, Vincent
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- New synthesis method of benzothiacyclopentadiene
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The invention discloses a novel synthesis method of benzothiacyclopentadiene, and belongs to the technical field of synthesis. The method comprises the following steps that: under an alkaline condition, chloroacetaldehyde and thiophenol undergo a Williamson condensation reaction to obtain thiophenyl acetaldehyde, the thiophenyl acetaldehyde undergoes a cyclization and dehydration reaction with a dehydrating agent under an acidic condition, water is added, layering is performed, an organic layer is taken, and reduced pressure distillation is performed to obtain the target product benzothiacyclopentadiene. The method has the advantages of simple operation, mild reaction, easy realization of industrialization, and high product yield.
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Paragraph 0034-0036; 0038-0040; 0050-0052
(2020/07/28)
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- Multikilogram Synthesis of a Potent Dual Bcl-2/Bcl-xL Antagonist. 2. Manufacture of the 1,3-Diamine Moiety and Improvement of the Final Coupling Reaction
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This paper describes the synthesis of kilogram quantities of the sulfonamide moiety 3 involved in a coupling reaction with acid moiety 2 to provide batches of drug candidate 1 for preclinical studies and first-in-human clinical trials. A first approach relying on a chiral separation furnished the desired enantiomer of 1,3-diamine 20, precursor of sulfonamide 3. An enantiomeric synthesis of 20 using the Ellman's chiral auxiliary coupled with an aza-Reformatsky reaction to control the stereochemistry is also discussed. Coupling conditions of the final step involving EDCI to provide 1 under a cGMP process are detailed. An alternative approach using N-(1-methanesulfonyl)benzotriazole is also presented.
- Hardouin, Christophe,Baillard, Sandrine,Barière, Fran?ois,Craquelin, Anthony,Grandjean, Mathieu,Janvier, Solenn,Le Roux, Stéphane,Penloup, Christine,Russo, Olivier
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p. 670 - 685
(2019/12/24)
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- Process for preparing sulfonamide compounds
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The invention relates to a process for preparing sulfonamide compounds. The sulfonamide compound is an inhibitor of Bcl-2/Bcl-xL and is prepared from a compound (3R)-1-(3-(4-(4-(4-(3-(2-(4-chlorphenyl)-1-isopropyl-4-methylsulfonyl-5-methyl-1H-pyrrole-3-yl
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- PROCESS FOR PREPARING SULFONAMIDE COMPOUNDS
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Provided are a process for preparing a sulfonamide compound which is an inhibitor of Bcl-2/Bcl-xL, including the compound (3R) -1- (3- (4- (4- (4- (3- (2- (4-chlorophenyl) -1-isopropyl-4-methylsulfonyl-5-methyl-1H-pyrrol-3-yl) -5-fluorophenyl) piperazine
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- 2-(phenylthio)ethylidene derivatives as anti-Trypanosoma cruzi compounds: Structural design, synthesis and antiparasitic activity
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Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi. The current chemotherapy is based on benznidazole, and, in some countries, Nifurtimox, which is effective in the acute phase of the disease, but its efficacy in the chronic p
- Cardoso, Marcos Veríssimo de Oliveira,de Oliveira Filho, Gevanio Bezerra,de Siqueira, Lucianna Rabelo Pessoa,Espíndola, José Wanderlan Pontes,Silva, Elany Barbosa da,Mendes, Andresa Pereira de Oliveira,Pereira, Valéria Rêgo Alves,de Castro, Maria Carolina Accioly Brelaz,Ferreira, Rafaela Salgado,Villela, Filipe Silva,Costa, Francielly Morais Rodrigues da,Meira, Cássio Santana,Moreira, Diogo Rodrigo Magalh?es,Soares, Milena Botelho Pereira,Leite, Ana Cristina Lima
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p. 191 - 203
(2019/07/16)
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- Direct access to α-sulfenylated amides/esters: Via sequential oxidative sulfenylation and C-C bond cleavage of 3-oxobutyric amides/esters
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An efficient, environmentally benign and unprecedented synthesis of various α-sulfenylated amides/esters has been developed under oxygen atmosphere. The reaction shows good functional group tolerance and excellent chemo/regioselectivity. All the desired products were obtained in moderate to excellent yields, even on the gram scale. Practically, the related α-thiol Weinreb amide can be readily transferred to a series of prospective compounds, and selenium atom can be introduced to the α-sites of the amides in high yields.
- Jiang, Yi,Deng, Jie-Dan,Wang, Hui-Hong,Zou, Jiao-Xia,Wang, Yong-Qiang,Chen, Jin-Hong,Zhu, Long-Qing,Zhang, Hong-Hua,Peng, Xue,Wang, Zhen
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p. 802 - 805
(2018/02/06)
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- Pummerer Cyclization Revisited: Unraveling of Acyl Oxonium Ion and Vinyl Sulfide Pathways
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Two viable pathways (vinyl sulfide and acyl oxonium ion) for the Pummerer cyclization have been unraveled that expand the reaction scope and capabilities. Use of Br?nsted-enhanced Lewis acidity was key to realization of the vinyl sulfide pathway, whereas selective complexation of the sulfur lone pair facilitated the unprecedented acyl oxonium ion pathway. Preliminary mechanistic investigations support these hypotheses. A range of substrates have been explored to understand the reaction parameters.
- Li, Xin,Carter, Rich G.
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p. 5541 - 5545
(2018/09/25)
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- A Stereoselective Synthesis of the Carbon Backbone of Phoslactomycin B
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A convergent synthesis of the entire carbon framework of phoslactomycin B is disclosed. An initial route aimed to create the C-8 tetrasubstituted stereocentre through regioselective intermolecular coupling between an internal alkyne and an allyl silyl ether, adopting Trost's protocol, followed by [2,3] sigmatropic rearrangement. But this was not successful. In a second approach, a propargylic sulfide was rearranged to give an unsaturated ketone. This was then treated with lithio acetonitrile to create the C-8 stereocentre selectively. The C-4 and C-5 stereocentres were introduced by a non-Evans syn-aldol reaction using Crimmins's protocol. The C-9 and C-11 carbinol centres were created by asymmetric transfer hydrogenation. The (Z,Z)-diene moiety was introduced by partial reduction of a diyne following Hansen's modification of the Boland reduction reaction.
- Raghavan, Sadagopan,Patel, Javed Sardar
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p. 2981 - 2997
(2017/06/06)
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- DIHYDROPYRONE COMPOUNDS AND HERBICIDES COMPRISING THE SAME
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The present invention provides a compound having an excellent efficacy for controlling weeds. A dihydropyrone compound of formula (I): wherein m is 1, 2 or 3; n is an integer of any one of 1 to 5; X represents O, S, S(O) or S(O)2; R1 /sup
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Paragraph 0129
(2014/06/23)
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- Borontribromide-mediated C-C bond formation in cyclic ketones: A transition metal free approach
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Borontribromide (BBr3) is a well-known demethylating agent. The current investigation was focused on a new application of borontribromide as a C-C bond forming agent in cyclic ketones. In this study, borontribromide mediated C-C bond formation reactions of tetralones, chromenone, thiochromenone and indanones were explored. A methoxy group containing ketones showed selective C-C bond formation reaction instead of demethylation of the methoxy group. MM2 steric energy calculations for the final products showed that the reaction favored the formation of exo- or endo-cyclic double bond containing products, depending upon their low MM2 steric energy in a specific frame structure, as observed in X-ray crystallography. A comprehensive crystallographic and pi-stacking analysis of product 10a demonstrated the formation of 10a as an enantiomeric mixture, and its centre of inversion was stabilized by a set of three unique pi-pi interactions.
- Ahmad, Imran,Pathak, Vinay,Vasudev, Prema G.,Maurya, Hardesh K.,Gupta, Atul
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p. 24619 - 24634
(2014/07/07)
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- Stereoselective synthesis of the C1-C8 subunit of peloruside A
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Two routes to the C1-C8 subunit of peloruside A are disclosed. The first route involving 14 steps exploits Krische's allylation, substrate controlled 1,3-asymmetric induction during bromohydrin formation from an alkene utilizing an intramolecular sulfinyl
- Raghavan, Sadagopan,Kumar, V. Vinoth
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p. 4835 - 4844
(2013/07/04)
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- Safe oxidation of sulfides into sulfoxides using SIBX
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SIBX is a stabilized (i.e., nonexplosive) formulation of the λ5-iodane 2-iodoxybenzoic acid IBX that can be used as a suspension in various organic solvents to oxidize safely sulfides into sulfoxides. Most yields are comparable to those obtaine
- Ozanne-Beaudenon, Aurélie,Quideau, Stéphane
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p. 5869 - 5873
(2007/10/03)
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- The chemistry of cyclic carbaphosphazenes: The first observation of (R 2PN)(ClCN)2 (R=Cl, Ph) as a reagent for the conversion of alcohols to aldehydes, ketones, and alkyl chlorides
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The oxidation of nine primary and secondary alcohols to the corresponding aldehydes and ketones has been carried out under mild conditions and in good yields using the cyclocarbaphosphazenes (R2PN)(ClCN)2 [R2P = Cl2 P(1), Ph2P(2)] along with dimethylsulfoxide. While both the P-Cl and C-Cl bonds of the carbaphosphazene can in principle bring about the reaction, we observed an increased preference for the C-Cl bonds over the P-Cl bonds in the oxidation of alcohol. Blocking the reactive P site on the heterocyclic ring with the phenyl groups was found to reduce the yields of the oxidized products, while blocking the C- sites with diethylamino groups resulted in no reaction. In addition, along with DMF, the same cyclocarbaphosphazene has been found to be useful for the conversion of alcohols to alkyl chlorides. Copyright Taylor & Francis Group, LLC.
- Behera, Nabakrushna,Mishra, Pradyumna Kumar,Elias, Anil J.
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p. 2445 - 2452
(2007/10/03)
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- 2-Iodylphenol ethers: Preparation, X-ray crystal structure, and reactivity of new hypervalent iodine(V) oxidizing reagents
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2-Iodylphenol ethers were prepared by the dimethyldioxirane oxidation of the corresponding 2-iodophenol ethers and isolated as chemically stable, microcrystalline products. Single-crystal X-ray diffraction analysis of 1-iodyl-2-isopropoxybenzene 8c and 1-iodyl-2-butoxybenzene 8d revealed pseudopolymeric arrangements in the solid state formed by intermolecular interactions between IO2 groups of different molecules. 2-Iodylphenol ethers can selectively oxidize sulfides to sulfoxides and alcohols to the respective aldehydes or ketones.
- Koposov, Alexey Y.,Karimov, Rashad R.,Geraskin, Ivan M.,Nemykin, Victor N.,Zhdankin, Viktor V.
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p. 8452 - 8458
(2007/10/03)
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- A biocatalytic route to enantioenriched, sulfanyl aldol products
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The aldol products derived from sulfur- or selenium containing acceptors were prepared by kinetic resolution in the presence of antibody 84G3 with enantiomeric excesses ranging from 56 to 70%. Much higher level of enantioselectivity was obtained (enantiomeric excesses all superior to 96%) for sulfanyl aldol products derived from thiomethoxyacetone with three different acceptors.
- Baker-Glenn,Ancliff,Gouverneur
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p. 7607 - 7619
(2007/10/03)
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- Reduction of ethanethiol esters to aldehydes
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Reduction of ethanethiol esters of α-amino acids to α-amino aldehydes by triethylsilane and catalytic palladium-on-carbon is described. α-Amino aldehydes with Boc, Cbz, or Fmoc protection could be obtained without racemization in high yield.
- Tokuyama, Hidetoshi,Yokoshima, Satoshi,Lin, Shao-Cheng,Li, Leping,Fukuyama, Tohru
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p. 1121 - 1123
(2007/10/03)
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- Novel one-pot preparation of 5-methoxylated indoline and indole derivatives using a hypervalent iodine(III) reagent
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A novel and efficient one-pot preparation of 1-tosylindoline and indole derivatives from N-tosylaniline derivatives (1) and activated olefin derivatives (2) using a hypervalent iodine(III) reagent, phenyliodine(III) bis(trifluoroacetate) (PIFA), is described.
- Tohma, Hirofumi,Watanabe, Hiroaki,Takizawa, Shinobu,Maegawa, Tomohiro,Kita, Yasuyuki
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p. 1785 - 1788
(2007/10/03)
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- Photochemical Reactions of Halo-/Aryl Sulfide-Substituted Alkyl Phenylglyoxylate, an Assessment of the Lifetime of the Intermediate 1,4-Biradical
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Photochemical reactions of several halo/aryl sulfide-substituted alkyl phenylglyoxylates (1) were studied. For 2′-bromo- (1b), 2′-iodo- (1c), 2′-(phenylthio)- (1d), and 2′-(phenylsulfinyl)- (1e) ethyl phenylglyoxylate, vinyl phenylglyoxylate (2), proposed to be the result of β-elimination from the 1,4-biradical formed by triplet state γ-hydrogen abstraction, is the dominant photoproduct. In the cases 1b and Id Norrish Type II products were also observed. Vinyl phenylglyoxylate (2) was not observed with 2′-chloroethyl (1a), 3′-bromopropyl (1f), and 3′-(phenylthio)propyl (1g) phenylglyoxylate. The lifetime of the 1,4-biradical intermediate is deduced from the competition between the β-elimination of the monoradical and the normal biradical decay. The triplet lifetime and the photoreaction efficiency of 1 were not significantly affected by halogen-substitution.
- Hu, Shengkui,Neckers, Douglas C.
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p. 7827 - 7831
(2007/10/03)
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- Synthesis of 2-(2,6-dichloro-4-pyridyl)-3-propargyl-5-ethyl-6-methyl- 4(3H)-pyrimidinone, a promising new herbicide
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A novel synthesis of the promising new herbicide 2-(2,6-dichloro-4-pyridyl)-3-propargyl-5-ethyl-6-methyl-4- (12) is reported which features (I) regioselective carbon, followed by nitrogen, dialkylation of an intermediate dianion, and 2 a tandem 'one-pot' sequence of reactions involving sigmatropic sulfoxide elimination, lithium chloride-induced demethylation of a carbomethoxy grouping, decarboxylation, and isomerization/aromatization.
- Taylor, Edward C.,Zhou, Ping,Tice, Colin M.,Lidert, Zev,Roemmele, Renee C.
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p. 4339 - 4342
(2007/10/03)
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- A Mild 10-I-4 Iodinane Oxide Oxidant for Primary and Secondary Alcohols
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Iodinane oxide 4 midly and rapidly oxidizes primary and secondary alsohols to their corresponding carbonyl products in excellent yield.Oxidations are carried out in CH2Cl2 at room temperature using 1.1 equivalent of oxidant.Other non-hydroxylic organic solvents may also be used.
- Stickley, Sharon H.,Martin, J. C.
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p. 9117 - 9120
(2007/10/02)
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- Sulfur-directed regioselective radical cyclization leading to β-lactams: Formal synthesis of (±)-PS-5 and (+)-thienamycin
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A new method for the synthesis of β-lactams by tributyltin hydride (Bu3SnH)-mediated radical cyclizations of N-ethenyl-α-bromo amides bearing sulfur-substituent(s) at the terminus of the N-vinylic bond is described. N-[2-(Phenylthio)ethenyl]-α-
- Ishibashi,Kameoka,Iriyama,Kodama,Sato,Ikeda
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p. 1276 - 1284
(2007/10/02)
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- Electroinitiated Oxygenation of Alkenyl Sulfides and Alkynes in the Presence of Thiophenol
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Electrolysis of alkenyl sulfides in the presence of thiophenol with bubbling of molecular oxygen gave the corresponding α-(phenylthio) carbonyl compounds with the consumption of a catalytic amount of electricity.An electroinitiated radical chain mechanism has been proposed.The reaction also took place without electrochemical initiation, but much (5-50 times) longer reaction time was required for the completion of the reaction.The potential utility of the present reaction in organic synthesis is demonstrated by the net 1,2-transposition of a phenylthio group and a carbonyl group.The electroinitiated oxygenation of ketene dithioacetals also proceeded smoothly to give the corresponding α-(phenylthio) thiol esters.It was also found that the electroinitiated oxygenation of alkynes in the presence of thiophenol gave α-(phenylthio) carbonyl compounds.A mechanism involving the initial formation of alkenyl sulfides has been proposed.
- Yoshida, Jun-ichi,Nakatani, Shogo,Isoe, Sachihiko
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p. 4855 - 4865
(2007/10/02)
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- Electro-initiated oxygenation of alkenylsilanes in the presence of thiophenol
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Electrolysis of alkenylsilanes in the presence of thiophenol with bubbling of molecular oxygen gave the corresponding α-phenylthio carbonyl compounds with the consumption of a catalytic amount of electricity. An electro-initiated radical chain mechanism i
- Nakatani, Shogo,Yoshida, Jun-Ichi,Isoe, Sachihiko
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p. 2011 - 2024
(2007/10/02)
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- Formation of Optically Active Aryloxyacetaldehyde Cyanohydrin Acetates with the Aid of a Microorganism
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Microorganisms that hydrolyze the one enantiomer of dl-phenoxyacetaldehyde cyanohydrin acetate were screened, and Bacillus coagulans isolated from soil was found to be the best.This bacterium was applied to the asymmetric hydrolysis of other aryloxyacetaldehyde derivatives to give satisfactory results.The effect of adding dimethyl sulfoxide to the medium is also described.
- Ohta, Hiromichi,Miyamae, Yoshitaka,Tsuchihashi, Gen-ichi
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p. 215 - 222
(2007/10/02)
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- Regiospecific Conversion of Alkenyl Sulphides to α-Sulphenylated Carbonyl Compounds by Oxygenation in the Presence of Thiophenol
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Regiospecific conversion of alkenyl sulphides to α-sulphenylated carbonyl compounds was achieved by oxygenation in the presence of thiophenol; electrolysis was found to be quite effective for initiation of the reaction.
- Yoshida, Jun-ichi,Nakatani, Shogo,Isoe, Sachihiko
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p. 1468 - 1470
(2007/10/02)
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- A Novel Rearrangement of Vinyl Sulphoxides
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Acid catalysed isopropenyl acetate treatment of vinyl sulphoxides results in a formal oxygen transposition from sulphur to the β-olefinic carbon via a presumed -sigmatropic rearrangement of an acetoxysulphonium salt.
- Lucchi, Ottorino De,Marchioro, Gaetano,Modena, Giorgio
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p. 513 - 514
(2007/10/02)
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