- Nitrone Formation by Reaction of an Enolate with a Nitro Group
-
Ketones with a 2-nitrophenyl group at the α-position were treated with sodium hydroxide in methanol at 60 °C. Under these conditions, enolates derived from the ketones intramolecularly reacted with the nitro group to form a variety of nitrones. Additional experimental results, including the unexpected isolation of N-hydroxyindolinone as a byproduct, led to a proposed reaction mechanism, occurring via an α-hydroxyketone. The resultant nitrones underwent inter- and intramolecular 1,3-dipolar cycloaddition with olefins to afford polycyclic isoxazolidines.
- Shimizu, Hiroaki,Yoshinaga, Kohei,Yokoshima, Satoshi
-
supporting information
p. 2704 - 2709
(2021/04/12)
-
- Synthetic method of bilastine intermediate
-
The invention discloses a synthetic method of a bilastine intermediate, and belongs to the technical field of organic synthesis. The method comprises the steps of (1) carrying out Friedel-Crafts reaction on benzene and alpha-methyl methacrylate in fluoroalcohol A at the temperature of -15 to 25 DEG C to obtain a compound A; (2) carrying out amine ester exchange reaction on the compound A and diisopropylamine at the temperature of 20-50 DEG C to obtain a compound B; and (3) carrying out Friedel-Crafts reaction on the compound B and ethylene oxide in fluoroalcohol B at the temperature of -15 to 25 DEG C to obtain the bilastine intermediate. According to the method, cheap benzene is taken as a raw material, and the intermediate alpha, alpha-dimethyl-4-(2-ethoxyl) phenylacetyldiisopropylamine is obtained through Friedel-Crafts alkylation, amine ester exchange and further Friedel-Crafts alkylation. In the step (2), a diisopropyl group is relatively large, so that the positioning effect is changed, and the problem of excessive isomers in the Friedel-Crafts alkylation process is avoided. The proportion of Friedel-Crafts alkylation para-position and meta-position products can be 95% or above.
- -
-
Paragraph 0011; 0026
(2021/05/12)
-
- Preparation method of aromatic hydrocarbon compound
-
The invention relates to a preparation method of an aromatic hydrocarbon compound, and particularly discloses a preparation method of a compound as shown in a formula I. The preparation method comprises the following step: in trifluoroacetic acid, under the action of triethylsilane, carrying out a reduction reaction as shown in the specification on a compound as shown in a formula II. The invention further discloses a preparation method of the compound 1, wherein the preparation method is simple in raw material, simple and convenient to operate, low in equipment requirement, small in environmental pollution, low in cost and very suitable for industrial production.
- -
-
Paragraph 0062-0065
(2020/12/30)
-
- Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation
-
Cyclopropanes are important structural motifs found in numerous bioactive molecules, and a number of methods are available for their synthesis. However, one of the simplest cyclopropanation reactions involving the intramolecular coupling of two C-H bonds on gem-dialkyl groups has remained an elusive transformation. We demonstrate herein that this reaction is accessible using aryl bromide or triflate precursors and the 1,4-Pd shift mechanism. The use of pivalate as the base was found to be crucial to divert the mechanistic pathway toward the cyclopropane instead of the previously obtained benzocyclobutene product. Stoichiometric mechanistic studies allowed the identification of aryl- and alkylpalladium pivalates, which are in equilibrium via a five-membered palladacycle. With pivalate, a second C(sp3)-H activation leading to the four-membered palladacycle intermediate and the cyclopropane product is favored. A catalytic reaction was developed and showed a broad scope for the generation of diverse arylcyclopropanes, including valuable bicyclo[3.1.0] systems. This method was applied to a concise synthesis of lemborexant, a recently approved anti-insomnia drug.
- Clemenceau, Antonin,Thesmar, Pierre,Gicquel, Maxime,Le Flohic, Alexandre,Baudoin, Olivier
-
supporting information
p. 15355 - 15361
(2020/10/20)
-
- Harnessing Applied Potential: Selective β-Hydrocarboxylation of Substituted Olefins
-
The construction of carboxylic acid compounds in a selective fashion from low value materials such as alkenes remains a long-standing challenge to synthetic chemists. In particular, β-addition to styrenes is underdeveloped. Herein we report a new electrosynthetic approach to the selective hydrocarboxylation of alkenes that overcomes the limitations of current transition metal and photochemical approaches. The reported method allows unprecedented direct access to carboxylic acids derived from β,β-trisubstituted alkenes, in a highly regioselective manner.
- Alkayal, Anas,Buckley, Benjamin R.,Malkov, Andrei V.,Montanaro, Stephanie,Tabas, Volodymyr,Wright, Iain A.
-
supporting information
(2020/02/13)
-
- ARYL-SUBSTITUTED ACETAMIDE AND PYRROLIDIN-2-ONE DERIVATIVES AND THEIR USE FOR THE TREATMENT OF SEIZURES
-
Aryl-substituted acetamide and pyrrolidin-2-one (γ-butyrolactam) derivatives have useful activity in the inhibition, prevention, or treatment of seizures. The derivatives may be useful in the treatment of epilepsy, including medically refractory epilepsy, and nerve agent poisoning.
- -
-
Paragraph 0055; 0057
(2019/06/09)
-
- HETEROCYCLIC COMPOUNDS
-
The present invention relates to compounds of the general formula (1) wherein the variables are defined as given in the description and claims. The invention further relates to uses of and to, processes and intermediates related to compounds of the general formula (I), wherein Q is wherein the substituents of I, Ia and Ib are as defined in description and claims.
- -
-
Page/Page column 75; 76; 79
(2018/07/29)
-
- Nickel-catalysed direct alkylation of thiophenes via double C(sp3)-H/C(sp2)-H bond cleavage: The importance of KH2PO4
-
A Ni-catalyzed oxidative C-H/C-H cross-dehydrogenative coupling (CDC) reaction was developed for constructing various highly functionalized alkyl (aryl)-substituted thiophenes. This method employs thiophenes and aliphatic (aromatic) amides that contain an 8-aminoquinoline as a removable directing group in the presence of a silver oxidant. The approach enables the facile one-step synthesis of substituted thiophenes with high functional group compatibility via double C-H bond cleavage without affecting C-Br and C-I bonds. DFT calculations verify the importance of KH2PO4 as an additive for promoting C-H bond cleavage and support the involvement of a Ni(iii) species in the reaction.
- Wang, Xie,Xie, Peipei,Qiu, Renhua,Zhu, Longzhi,Liu, Ting,Li, You,Iwasaki, Takanori,Au, Chak-Tong,Xu, Xinhua,Xia, Yuanzhi,Yin, Shuang-Feng,Kambe, Nobuaki
-
supporting information
p. 8316 - 8319
(2017/07/26)
-
- An electrochemical method for carboxylic ester synthesis from N-alkoxyamides
-
An electrochemical method for the synthesis of carboxylic as well as hindered esters from N-alkoxyamides has been reported. The electrochemical reaction proceeds through constant current electrolysis (CCE) by taking advantage of the dual role of n-Bu4NI (TBAI) as the redox catalyst as well as the supporting electrolyte. Besides providing mild reaction conditions, the present protocol is free from external oxidants and conducting salts, thereby generating nitrogen as the nonhazardous side product. Additionally, the developed procedure is highly advantageous due to its short reaction time, wide substrate scope, and gram-scale synthesis.
- Subramanian, Kripa,Yedage, Subhash L.,Bhanage, Bhalchandra M.
-
p. 10025 - 10032
(2018/05/31)
-
- Continuous in situ electrogenaration of a 2-pyrrolidone anion in a microreactor: application to highly efficient monoalkylation of methyl phenylacetate
-
We have successfully demonstrated effective generation of an electrogenerated base (EGB) such as the 2-pyrrolidone anion and its rapid use for the following alkylation reaction in a flow microreactor system without the need for severe reaction conditions. The key feature of the method is effective and selective preparation of monoalkylated products.
- Matsumura, Yoshimasa,Kakizaki, Yoshinobu,Tateno, Hiroyuki,Kashiwagi, Tsuneo,Yamaji, Yoshiyuki,Atobe, Mahito
-
p. 96851 - 96854
(2015/11/24)
-
- Copper-Catalyzed Formation of α-Alkoxycycloalkenones from N-Tosylhydrazones
-
The combination of 20 mol % of copper iodide and lithium tert-butoxide triggers the formation of a broad range of substituted, functionalized α-alkoxy 2H-naphthalenones from readily available N-tosylhydrazones. The data suggests that this transformation occurs through cycloaddition of a copper carbenoid with an ester, followed by a Lewis acid-catalyzed [1,2] alkyl shift of the in situ generated alkoxyepoxide intermediate. The combination of 20 mol % of copper iodide and lithium tert-butoxide triggers the formation of a broad range of substituted, functionalized α-alkoxy 2H-naphthalenones from readily available N-tosylhydrazones. The reaction proceeds by the cycloaddition of a copper carbenoid with an ester, and a subsequent Lewis acid-catalyzed [1,2] alkyl shift of the in situ generated alkoxyepoxide intermediate.
- Su, Naijing,Theorell, Juliana A.,Wink, Donald J.,Driver, Tom G.
-
p. 12942 - 12946
(2015/11/02)
-
- Aerobic Copper-Catalyzed O-Methylation with Methylboronic Acid
-
The oxidative coupling of alkylboronic acids with oxygen nucleophiles offers a strategy for replacing toxic, electrophilic alkylating reagents. Although the Chan-Lam reaction has been widely applied in the arylation of heteroatom nucleophiles, O-alkylation with boronic acids is rare. We report a Cu-catalyzed nondecarboxylative methylation of carboxylic acids with methylboronic acid that proceeds in air with no additional oxidant. An isotope-labeling study supports an oxidative cross-coupling mechanism, in analogy to that proposed for Chan-Lam arylation.
- Jacobson, Clare E.,Martinez-Mu?oz, Noelia,Gorin, David J.
-
p. 7305 - 7310
(2015/07/28)
-
- OLEFIN SUBSTITUTED OXINDOLES HAVING AMPK ACTIVITY
-
The present invention relates to compounds of formula (I), which have valuable pharmacological properties, in particular are activators of AMPK and which are therefore useful in the treatment of certain disorders that can be prevented or treated by activation of this receptor. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.
- -
-
Page/Page column 107; 108
(2015/01/07)
-
- SPIRO-SUBSTITUTED OXINDOLE DERIVATIVES HAVING AMPK ACTIVITY
-
The present invention relates to compounds of formula (I), which have valuable pharmacological properties, in particular are activators of AMPK and which are therefore useful in the treatment of certain disorders that can be prevented or treated by activation of this receptor. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.
- -
-
Page/Page column 113
(2015/01/07)
-
- Methoxycarbonylation of olefins catalyzed by palladium(II) complexes containing naphthyl(diphenyl)phosphine ligands
-
Palladium(II) complexes containing phosphine donor ligands derived from naphthyl(diphenyl)phosphine were synthesized and characterized by NMR and elemental analysis. The complexes were studied as catalyst precursors in the methoxycarbonylation reaction of several aromatic and aliphatic olefins under mild conditions. The catalysts reported high chemoselectivities (over 96%) and regioselectivities between 44% and 93% for different olefins. The best results were obtained over a styrene substrate with 97% of conversion after 6 h of reaction, with high regioselectivity (93%). Kinetic studies permitted the determination of the rate law (v-‰=-‰k [substrate] 1.21±0.02 [catalyst]0.94±0.11 [acid] 0.52±0.03 [MeOH]0.53±0.05 [CO] 0.65±0.03) for methoxycarbonylation of styrene.
- Zolezzi, Santiago,Moya, Sergio A.,Valdebenito, Gonzalo,Abarca, Gabriel,Parada, Jose,Aguirre, Pedro
-
p. 364 - 371
(2014/05/06)
-
- Catalytic methyl transfer from dimethylcarbonate to carboxylic acids
-
Although methylation reactions are commonplace, currently used reagents are hazardous, toxic, and/or unstable. Dimethylcarbonate has been put forth as an inexpensive, nontoxic, and green potential methylating reagent. Herein we report a general, base-catalyzed methyl transfer from dimethylcarbonate to carboxylic acids. High selectivity for esterification is observed even in the presence of unprotected phenols, and the mild reaction conditions enable conservation of stereochemistry at epimerizable stereocenters. Isotope-labeling studies suggest a mechanism proceeding by direct methyl transfer from dimethylcarbonate to the substrate.
- Ji, Yuan,Sweeney, Jessica,Zoglio, Jillian,Gorin, David J.
-
p. 11606 - 11611
(2013/12/04)
-
- Synthesis, spectral characterization and biological evaluation of a novel series of 6-arylsubstituted-3-[2-(4-substitutedphenyl)propan-2-yl]-7H-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazines
-
On account of the reported anticancer activity of triazolothiadiazines, we have synthesized a novel series of 6-arylsubstituted-3-[2-(4-substitutedphenyl) propan-2-yl]-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and tested for in-vitro cytotoxicity by trypan blue exclusion and MTT assay. These compounds were also evaluated for their in-vivo anthelmintic activity, as well as in-vitro antimicrobial studies. Amongst the tested compounds, the compound 7j was the most promising cytotoxic agent with IC50 value of 10.54 μM in MCF-7 cells. The compounds 7l and 7q exhibited excellent anthelmintic activity. The compounds 7d, 7f, 7j, 7l, 7o, 7p and 7r showed good antibacterial activity, whereas compounds 7e and 7k exhibited excellent antifungal activity. The structures of newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR and LCMS analysis.
- Puthiyapurayil, Pushpan,Poojary, Boja,Chikkanna, Chandrashekhar,Buridipad, Sunil Kumar
-
p. 407 - 416
(2013/01/15)
-
- Synthesis of [2H5]-ebastine fumarate and [ 2H5]-hydroxyebastine
-
This study describes the synthesis of deuterium-labelled ebastine fumarate and its deuterium-labelled metabolite hydroxyebastine. The synthesis of the two desired compounds both used [2H5]-bromodiphenylmethane as deuterium-labelled reagent, which was synthesized beforehand in three steps. [2H5]-ebastine was synthesized in further three steps with a 27% overall yield and [2H5]-hydroxyebastine was synthesized in further seven steps with a 13% overall yield.
- Yu, Zhoujie,Wang, Wei,Chen, Liqin
-
experimental part
p. 352 - 356
(2012/06/01)
-
- Generation of carbanions through stibine-metal and bismuthine-metal exchange reactions and its applications to precision synthesis of ω-end-functionalized polymers
-
Generation of carbanions from organostibines and organobismuthines through heteroatom-metal exchange reactions was examined from synthetic and mechanistic viewpoints. The exchange reaction proceeded spontaneously upon treatment with various organometallic reagents, such as alkyl lithiums, tetraalkyl zincates, and alkyl magnesium halides to afford the corresponding carbanions quantitatively. Due to the high reactivity of these heteroatom compounds, the exchange reactions took place exclusively even in the presence of various polar functional groups, which potentially react with organometallic species. The advantage of this method was exemplified by the end-group transformation of living polymers that bear these heteroatom species at the ω-polymer end, prepared by using organostibine and bismuthine-mediated living radical polymerizations. Various polymers that bear polar functional groups and acidic hydrogen-for example, poly(methyl methacrylate), poly(butyl acrylate), poly(N-isopropyl acrylamide), and poly(2-hydroxyethyl methacrylate)-could be used in the exchange reactions, and subsequent trapping with electrophiles afforded the corresponding polymers with controlled molecular weights, molecular weight distributions, and end-group functionalities. Competition experiments showed that organostibines and organobismuthines were among the most reactive heteroatom compounds towards organometallic reagents and that their high reactivity was responsible for the high chemoselectivity in the exchange reaction. All's well that ends well: The generation of carbanions from organostibine and -bismuthine compounds was achieved thorough a heteroatom-metal exchange reaction (see scheme). The highly chemoselective exchange reaction could be applied to precision synthesis of varieties of ω-end- functionalized polymers that possess a polar functional group.
- Kayahara, Eiichi,Yamada, Hiroto,Yamago, Shigeru
-
supporting information; experimental part
p. 5272 - 5280
(2011/06/20)
-
- Synthesis and biological activities of a novel series of 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles containing gem-dimethylbenzyl moiety
-
A novel series of 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4- thiadiazoles (6a-r) containing gem-dimethyl benzyl moiety were prepared by the condensation of 4-amino-3-aryl/aralkyl substituted-5-mercapto-1,2,4-triazoles (5a-c) with various fluoro substituted aromatic acids in the presence of POCl3. IR, 1H NMR, 13C NMR, 2D NMR (COSY), and mass spectral data confirmed the structures of all the synthesized compounds. All the compounds were also screened for their antibacterial, antifungal and analgesic activities. Compounds 6b, 6d, 6f, 6g, 6h, 6i, 6m, 6n, 6o, 6p, and 6r exhibited promising antibacterial and compounds 6a, 6d, 6f, 6g, 6h, 6k, 6m, 6o, 6p, and 6q showed significant analgesic activities.
- Puthiyapurayil, Pushpan,Poojary, Boja,Kumar, Sunil,Hunnur, Raveendra
-
experimental part
p. 998 - 1005
(2011/11/06)
-
- Mechanistic switch via subtle ligand modulation: Palladium-catalyzed synthesis of α,β-substituted styrenes via C-H bond functionalization
-
A new catalyst system able to efficiently perform the synthesis of styrenes via C-H bond functionalization and a subtle ligand modification are described. The high level of activity achieved allows for the synthesis of highly functionalized α,β-substituted styrenes, even the elusive E-configured trisubstituted olefins, in a regio- and stereoselective manner. Mechanistic experiments allowed for the identification of the corresponding synthetic intermediates.
- Flores-Gaspar, Areli,Martin, Ruben
-
supporting information; experimental part
p. 1223 - 1228
(2011/06/26)
-
- A novel synthetic route to 2-arylalkanoic acids by a ruthenium-catalyzed chemoselective oxidation of furan rings
-
An efficient two-step synthesis of 2-arylalkanoic acids from 1-arylalkanols is described. Firstly, 1-arylalkylfuran derivatives were synthesized in high yields by the metal triflate catalyzed Friedel-Crafts alkylation of 2-methylfuran with 1-arylalkanols without employing anhydrous conditions. The chemoselective oxidation of the furan ring in 1-arylalkylfurans to carboxylic acid was then investigated. In a solvent system of hexane-EtOAc/H2O (1:3:4), the furan ring was selectively oxidized with 7 equivalents of NaIO 4 by using 0.5 mol% RuCl3 as catalyst to give 2-arylalkanoic acids in good yields. The selectivity of ruthenium oxidation was controlled by the solvent ratio of hexane-EtOAc. Georg Thieme Verlag Stuttgart.
- Noji, Masahiro,Sunahara, Haruka,Tsuchiya, Ken-Ichi,Mukai, Toru,Komasaka, Ayako,Ishii, Keitaro
-
experimental part
p. 3835 - 3845
(2009/07/04)
-
- Palladium-catalyzed-arylattion of esters With chloroarenes
-
Palladium-catalyzed α-arylations of esters with chloroarenes are reported. The reactions of chloroarenes with the sodium enolates of tert-butyl propionate and methyl isobutyrate occur in high yields with 0.2-1 mol % of {[P(f-Bu)3]PdBr}2/s
- Hama, Takuo,Hartwig, John F.
-
supporting information; experimental part
p. 1549 - 1552
(2009/04/10)
-
- INDUSTRIAL PROCESS OF FEXOFENADINE HYDROCHLORIDE WITH CONTROLLED SIDE PRODUCTS
-
The present invention relates to a process for the preparation of Anhydrous Fexofenadine Hydrochloride with controlled level of side products. Another aspect of the present invention is purification of Fexofenadine base free of meta isomer of fexofenadine base and fexofenadinone.
- -
-
Page/Page column 4; 6-7; 10
(2008/06/13)
-
- Amide derivatives as somatostatin receptor 5 antagonists
-
This invention is concerned with compounds of the formula wherein R1 to R5, R5′ and A are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The invention further relates to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and/or prevention of diseases which are associated with the modulation of SST receptors subtype 5.
- -
-
Page/Page column 31
(2008/06/13)
-
- Highly regioselective anti-markovnikov palladium-borate-catalyzed methoxycarbonylation reactions: Unprecedented results for aryl olefins
-
(Chemical Equation Presented) A general, highly efficient and regioselective methoxycarbonylation, by means of a palladium-salicylicborate- catalyzed protocol, of terminal alkyl and aryl olefins is described. The substrates include aliphatic alkenes, allylbenzenes, and styrene derivatives. The yields are very good (60-92%) and the regioselectivity, in favor of the linear ester, is up to quantitative - unprecedented in the case of styrenes.
- Vieira, Tiago O.,Green, Mike J.,Alper, Howard
-
p. 6143 - 6145
(2007/10/03)
-
- FEXOFENADINE POLYMORPHS AND PROCESSES OF PREPARING THE SAME
-
Anhydrous crystalline fexofenadine hydrochloride Form C, crystalline fexofenadine acetate monohydrate Form D, crystalline fexofenadine acetate dihydrate Form E and crystalline fexofenadine free base monohydrate Form F, processes of preparing the same, pharmaceutical compositions thereof, therapeutic uses thereof and methods of treatment therewith.
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-
Page/Page column 23
(2008/06/13)
-
- Anti-infective agents
-
Compounds having the formula are hepatitis C (HCV) polymerase inhibitors. Also disclosed are a composition and method for inhibiting hepatitis C (HCV) polymerase, processes for making the compounds, and synthetic intermediates employed in the processes.
- -
-
Page/Page column 71
(2008/06/13)
-
- ANTI-INFECTIVE AGENTS
-
Compounds having the formula (I) are hepatitis C (HCV) polymerase inhibitors. Also disclosed are a composition and method for inhibiting hepatitis C (HCV) polymerase, processes for making the compounds, and synthetic intermediates employed in the processes.
- -
-
Page/Page column 141
(2010/02/11)
-
- A facile conversion of aryl alkyl ketones into methyl 2-arylalkanoates using poly[4-(diacetoxyiodo)styrene]
-
Treatment of aryl alkyl ketones with poly[4-(diacetoxyiodo)styrene] and trimethyl orthoformate in the presence of sulfuric acid followed by hydrolysis afforded methyl 2-arylalkanoates in good yields. The polymeric reagent can be regenerated and reused as an environmentally benign reagent.
- Sheng, Shou-Ri,Zhong, Ming-Hua,Liu, Xiao-Ling,Luo, Qiu-Yan,Chen, Hui-Zong
-
p. 392 - 393
(2007/10/03)
-
- Palladium-Catalyzed Arylation of Trimethylsilyl Enolates of Esters and Imides. High Functional Group Tolerance and Stereoselective Synthesis of α-Aryl Carboxylic Acid Derivatives
-
A general procedure for the palladium-catalyzed arylation of trimethylsilyl enolates of esters and imides is reported. In the presence of ZnF2 or Zn(O-t-Bu)2 as an additive, the trimethylsilyl enolates of esters, including those bearing α-alkoxy derivatives, underwent arylation in high yield with high functional group tolerance. This arylation chemistry was extended to ester derivatives bearing chiral auxiliaries to form new tertiary stereocenters. The arylation of imides bearing the Evans auxiliary proceeded with selectivities up to 90% de. Further, the arylation of the ketal developed by Ley provided α-aryl glycolates with excellent diastereoselectivities (90 to >98% de). This reaction provides a convenient route to the synthesis of enantiopure α-aryl-α-hydroxy esters. Reactions conducted with Zn(O-t-Bu)2 as an additive occurred at room temperature to give enhanced diastereoselectivities with both chiral reagents. Mechanistic studies showed that the reaction conditions are neutral enough that the observed diastereomeric ratios reflect kinetic selectivities.
- Liu, Xiaoxiang,Hartwig, John F.
-
p. 5182 - 5191
(2007/10/03)
-
- 1,1-DISUBSTITUTED CYCLOALKYL DERIVATIVES AS FACTOR XA INHIBITORS
-
The present application describes 1,1-disubstituted cycloalkyl compounds and derivatives thereof, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of factor Xa.
- -
-
-
- Palladium-catalyzed α-arylation of esters and amides under more neutral conditions
-
Two procedures for the ∞-arylation of carbonyl compounds under conditions that are more neutral than those of reactions of aryl halides with alkali metal enolates are reported. The first procedure rests upon the development of catalysts bearing the hindered pentaphenylferrocenyl di-tert-butylphosphine (Q-phos) and the highly reactive dimeric Pd(I) complex {P(t-Bu)3]PdBr}2. By this procedure, zinc enolates prepared from ∞-bromo esters and amides react with aryl halides to form ∞-aryl esters and amides in high yields under mild conditions with 1-2 mol % catalyst and with remarkable functional group tolerance. By the second procedure, silyl ketene and silyl ketimine acetals react with aryl bromides in the presence of substoichiometric zinc fluoride, 1 mol % Pd(dba)2, and 2 mol % P(t-Bu)3 in DMF solvent at 80 °C. Reactions of zinc tert-butyl acetate and propionate enolates and trimethylsilyl ketene acetals of tert-butyl propionate and methyl isobutyrate with aryl bromides bearing electron-donating and potentially reactive, base-sensitive electron-withdrawing groups and with pyridyl bromides are reported. In addition, the diastereoselective coupling of phenyl bromide with an imide enolate bearing the Evans auxiliary is reported, and this study shows that racemization of base-sensitive stereocenters does not occur during the coupling process under these more neutral conditions. Copyright
- Hama, Takuo,Liu, Xiaoxiang,Culkin, Darcy A.,Hartwig, John F.
-
p. 11176 - 11177
(2007/10/03)
-
- Efficient synthesis of α-aryl esters by room-temperature palladium-catalyzed coupling of aryl halides with ester enolates
-
A catalytic amount of Pd(dba)2 ligated by either carbene precursor N,N′-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium (1) or P(t-Bu)3 mediated the coupling of aryl halides and ester enolates to produce α-aryl esters in high yields at room temperature. The reaction was highly tolerant of functionalities and substitution patterns on the aryl halide. Improved protocols for the selective monoarylation of tert-butyl acetate and the efficient arylation of α,α-disubstituted esters were developed with LiNCy2 as base and P(t-Bu)3 as ligand. In addition, tert-butyl esters, such as those of Naproxen and Flurbiprofen, were prepared from tert-butyl propionate and aryl bromides in high yields in the presence of Pd(dba)2 and the hindered, saturated heterocyclic carbene ligand precursor.
- Jorgensen, Morten,Lee, Sunwoo,Liu, Xiaoxiang,Wolkowski, Joanna P.,Hartwig, John F.
-
p. 12557 - 12565
(2007/10/03)
-
- Intermediates useful for the preparation of antihistaminic piperidine derivatives
-
The present invention is related to a novel intermediates and processes which are useful in the preparation of certain antihistaminic piperidine derivatives of the formula whereinW represents —C(=O)— or —CH(OH)—;R1 represents hydrogen or hydroxy;R2 represents hydrogen;R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;n is an integer of from 1 to 5;m is an integer 0 or 1;R3 is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched each of A is hydrogen or hydroxy; andpharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0.
- -
-
Page column 47-48
(2008/06/13)
-
- Development of orally active nonpeptidic inhibitors of human neutrophil elastase
-
5-Amino-2-phenylpyrimidin-6-ones, some of their desamino derivatives, and miscellaneous derivatives were synthesized and biologically evaluated on both in vitro activity and oral activity in an acute hemorrhagic assay. These compounds contained an α-keto-1,3,4-oxadiazole moiety to bind covalently to the Ser-195 hydroxy group of human neutrophil elastase (HNE). Among those tested, compounds 11a-c,e,i-l(F), 11d,e,k(H), 21d,e,k(F), and 21d,e(H) showed a good oral profile. RS-Mixture 3(H) was selected for clinical evaluation based on its oral potency, duration of action, enzyme selectivity, safety profile, and ease of synthesis. Structure -activity relationships (SARs) are discussed.
- Ohmoto,Yamamoto,Okuma,Horiuchi,Imanishi,Odagaki,Kawabata,Sekioka,Hirota,Matsuoka,Nakai,Toda,Cheronis,Spruce,Gyorkos,Wieczorek
-
p. 1268 - 1285
(2007/10/03)
-
- Electrophilic peptide analogs as inhibitors of trypsin-like enzymes
-
This invention relates to electrophilic dipeptide analogs conjugated to an N,N-disubstituted alpha -amino acid as inhibitors of trypsin-like serine protease enzymes.
- -
-
-
- A new synthesis of carboxyterfenadine (fexofenadine) and its bioisosteric tetrazole analogs
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A new synthesis of carboxyterfenadine (4), based on the conversion of a α-halo-alkylarylketone into the corresponding substituted 2-arylalkanoic ester, is described. The enantioselective synthesis of its two bioisosteric tetrazole analogs together with preliminary biological results are reported. Copyright (C) 1999 Elsevier Science S.A.
- Di Giacomo, Barbara,Coletta, Donato,Natalini, Benedetto,Ni, Ming-Hong,Pellicciari, Roberto
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p. 600 - 610
(2007/10/03)
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- Rational design of boropeptide thrombin inhibitors: β,β-Dialkyl-phenethylglycine P2 analogs of DuP 714 with greater selectivity over complement factor I and an improved safety profile
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The potent boropeptide thrombin inhibitor DuP 714 caused side effects in laboratory animals that appear to be related to its ability to inhibit complement factor I, thereby activating the complement cascade. Using X-ray crystal structure information, we have designed compounds that have greater selectivity for thrombin over factor I and that have reduced tendency to produce these side effects.
- Fevig, John M.,Buriak Jr., Joseph,Cacciola, Joseph,Alexander, Richard S.,Kettner, Charles A.,Knabb, Robert M.,Pruitt, James R.,Weber, Patricia C.,Wexler, Ruth R.
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p. 301 - 306
(2007/10/03)
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- Spectroscopy and photochemistry of phenylacetic acid esters and related substrates. The stereoelectronic dependence of the aryl/carboxyl bichromophore interaction
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The 254-nm-initiated Norrish Type II photofragmentation of the ethoxyethyl esters of a series of phenylacetic acids (1b-4b) has been studied in order to further elaborate the aryl/ester interaction that is photochemically and photophysically evident in these systems. The ethoxyethyl ester of benzonorbornene-1-carboxylic acid (5) has also been prepared and studied, as has a rigid tricyclic lactone (6) which places the chromophores in an optimal stereoelectronic relationship for interaction. The experimental work is accompanied by Hartree-Fock (HF), Natural Bond Orbital (NBO), and Configuration Interaction with Single Excitations (CIS) calculations on the methyl esters of phenylacetic acid (1a) and α-methoxyphenylacetic acid (4a). The calculations confirm extensive through-space (TS) and through-bond (TB) interactions between the aryl and ester π* orbitals but fail to provide conformational or electronic arguments to explain the unusually high reactivity of the α-methoxy series.
- Kasper,Nash,Morrison
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p. 2792 - 2798
(2007/10/02)
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- Selective Mono-methylation of Arylacetonitriles and Methyl Arylacetates by Dimethyl Carbonate
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Both arylacetonitriles and methyl arylacetates react with dimethyl carbonate (DMC) (20 molar excess) at 180 - 200 deg C in the presence of K2CO3 to produce monomethylated 2-arylpropionitriles and methyl 2-arylpropionates, respectively, with a selectivity >99.5percent.The reaction, with wide application, proceeds by DMC acting as a methoxycarbonylating agent towards the ArCH-X anion (X = CN, CO2Me) and as a methylating agent to ArC-(CO2Me)X.DMC also proved to be the best solvent for such reactions.
- Selva, Maurizio,Marques, Carlos Alberto,Tundo, Pietro
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p. 1323 - 1328
(2007/10/02)
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- Saturated heterocyclic carboxamide derivatives
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A saturated heterocyclic carboxamide derivative of the following general formula (I) and salts thereof which have platelet activating factor (PAF) antagonizing activity. STR1
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- 13C magnetic resonance studies. 142. The fate of highly substituted acyclic ketones in strong base: β-enolization, Haller-Bauer cleavage, and an alkyl to aryl acyl shift
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Di-tert-butyl ketone (2a), 5,5,7,7-tetramethyl-6-undecanone (2b), and 2,4-dimethyl-2,4-diphenyl-3-pentanone (2d) have been found to undergo slow rearrangement by β-proton abstraction from the α-methyl groups upon treatment with t-BuO-/t-BuOH/>185 deg C.This is in contrast to the absence of such rearrangement in cyclic systems.It is the only significant process observed for 2a and 2b, whereas with 2d and its monomethyl analog 22 Haller-Bauer type cleavage and an unprecedented 1,3-acyl shift from sp3 to sp2 carbon accompany the β-enolate rearrangement.The rates of 1H/2H exchange of the methyl protons in 2a, b were found to be similar to those reported for a variety of cyclic systems but this exchange does not occur in 2d, where only aryl proton exchange was observed.
- Dyllick-Brenzinger, Rainer A.,Patel, Vijay,Rampersad, Mollin B.,Stothers, J. B.,Thomas, Shirley E.
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p. 1106 - 1115
(2011/08/10)
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- Electroorganic Chemistry. 124. Electroreductive Intramolecular Coupling of α-(ω-Bromoalkyl) β-Keto Esters
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Intramolecular coupling occurs when cyclic α-(bromomethyl) β-keto esters are electrochemically reduced in the presence of trimethylsilyl chloride and one-carbon ring-enlarged products are obtained in reasonable yields.Electroreduction of α-(γ-bromopropyl) β-keto esters also affords the corresponding five-membered cyclized products and/or the corresponding ring-opened compounds.The ease of ring opening of the cyclized products is highly influenced by their stereoconfiguration.Electroreduction of α-(β-bromoethyl) β-keto ester gives the product formed by the reductive elimination of the bromoethyl group whereas α-(δ-bromobutyl) β-keto ester yields the product of the reductive elimination of bromine.This electroreductive intramolecular coupling is initiated by the reduction of the carbon-bromine bond and proceeds through a carbanion intermediate.
- Shono, Tatsuya,Kise, Naoki,Uematsu, Nobuyuki,Morimoto, Shinji,Okazaki, Eiichi
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p. 5037 - 5041
(2007/10/02)
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- 2,5,6,7-tetranor-4,8-inter-m-phenylene PGI2 derivatives
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Disclosed herein are novel prostaglandin I2 (PGI2) derivatives exhibiting excellent in vivo duration and activities, said derivatives being represented by the general formula: STR1 wherein R1, X, R2 and R3 are as defined herein.
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- 1,2-Migrations in Free Radicals Related to Coenzyme B12 Dependent Rearrangements
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The free radicals XC(CH3)(COOR)CH2., where X=C(=O)Me (1), C(=O)SEt (2), C(=O)OEt (3), C(=CH2)Me (4), and C6H5 (5), were generated by reaction of the corresponding bromides with (n-Bu)3SnH.The rates of rearrangement involving 1,2-migration of X (to form .C(CH3)(COOR)(CH2X)) were measured in competition with trapping by (n-Bu)3SnH.The measurements yielded the following rearrangement rate constants, kr, and activation parameters, ΔH+ and ΔS+: (1) 1.2E4 s-1 at 45 deg C, 11.0 kcal/mol, -4 cal/mol.K; (2) 23.5 s-1 at 60.5 deg C, 13.8 kcal/mol, -11 cal/mol.K; (3) -1 at 113 deg C; (4) 3.0E5 s-1 at 45 deg C, 10.0 kcal/mol, -2 cal/mol.K; (5) 5.0E3 s-1 at 61 deg C.From the results of crossover experiments it is concluded that the rearrangements of 1 and 2 are intramolecular processes, probably proceeding through cyclopropyloxy radical intermediates or transition states.The carbanions corresponding to 1-5 (i.e., XC(CH3)(COOR)CH2-, generated by reduction of the corresponding bromides with sodium naphthalene) also rearrange rapidly but, in each case, with some contribution from migration of the ester group.This represents the first demonstration of spontaneous 1,2-migration of a thioester group in a free radical and models the coenzyme B12 dependent methylmalonyl-CoA mutase rearrangement.The results support a free-radical rearrangement mechanism for the latter reaction.
- Wollowitz, Susan,Halpern, Jack
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p. 3112 - 3120
(2007/10/02)
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- Photochemical Reaction of 1,4-Naphthalenedicarbonitrile with Alkylbenzenes and Bibenzyls
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The photochemical reaction of 1,4-naphthalenedicarbonitrile with some alkylbenzenes and bibenzyls has been examined.A unitary mechanistic picture is formulated on the basis of product study, deuteration experiments, and fluorescence and reaction quantum yield measurements.Proton transfer within the singlet radical ion pair followed by in-cage cycloaddition of the two radicals yields stereoselectively 5,11-methanodibenzo cyclooctene derivatives (8).Reaction of benzyl radicals (formed by protolysis or, for radical cations having no benzylic proton, by C-C bond cleavage) with unprotonated NDN.- leads, again stereoselectively, to 2-benzyl-1,2-dihydronaphtalenes (9).Escape of the donor radical cation and following C-H or C-C bond cleavage leads to a different product, thus, benzyl radicals are trapped by NDN to yield substitution products (11) or recombine.Benzyl cations are trapped by nucleophiles.
- Albini, Angelo,Fasani, Elisa,Mella, Mariella
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p. 4119 - 4125
(2007/10/02)
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- Facile Synthesis of 2-Alkoxy-2-aryloxiranes
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Tertiary α-bromoalkyl aryl ketones 1 were converted into 2-alkoxy-2-aryloxiranes 4 exclusively by reaction with excess potassium carbonate in the corresponding dry alcohol.Silver carbonate in a dry alcohol with these α-bromo ketones yielded competitively formation of 2-alkoxyoxiranes and semi-benzilic Favorskii rearrangement (-> 5), while silver hexafluoroantimonate in the same medium afforded the latter rearrangement reaction exclusively.
- Kimpe, Norbert De,Buyck, Laurent De,Verhe, Roland,Schamp, Niceas
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p. 3631 - 3636
(2007/10/02)
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