- Aza-Matteson Reactions via Controlled Mono-and Double-Methylene Insertions into Nitrogen-Boron Bonds
-
Boron-homologation reactions represent an efficient and programmable approach to prepare alkylboronates, which are valuable and versatile synthetic intermediates. The typical boron-homologation reaction, also known as the Matteson reaction, involves formal carbenoid insertions into C-B bonds. Here we report the development of aza-Matteson reactions via carbenoid insertions into the N-B bonds of aminoboranes. By changing the leaving groups of the carbenoids and altering Lewis acid activators, selective mono- and double-methylene insertions can be realized to access various α- and β-boron-substituted tertiary amines, respectively, from common secondary amines. The derivatization of complex amine-containing bioactive molecules, diverse functionalization of the boronate products, and sequential insertions of different carbenoids have also been achieved.
- Xie, Qiqiang,Dong, Guangbin
-
supporting information
p. 14422 - 14427
(2021/09/29)
-
- Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients
-
Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients, are provided. Certain of the systems and methods described herein are capable of manufacturing multiple chemical products without the need to fluidically connect or disconnect unit operations when switching from one making chemical product to making another chemical product.
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Page/Page column 37; 38
(2020/12/14)
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- Naphthyl-derived orthometalated RUII-NHC complexes: Effect of the NHC donors and/or substitution pattern on their synthesis and catalytic activity
-
Naphthyl-derived orthometalated RuII-NHC complexes have been developed for catalytic applications considering the stereoelectronic profiles of the NHC ligands, which can be modified easily via alteration of the NHC donors (ImNHC/1,2,4tzNHC) as well as their substitution pattern at the naphthyl ring. The azolium salts [(2a?c)-H]Br, precursors for the NHC ligands, react with [Ru(p-cymene)Cl2]2 in the presence of a base to deliver the ortho-metalated RuII-NHC complexes 3a?c with the general formula [(NHC)Ru(p-cymene)Br]. Orthometalation in these complexes can be exploited for further functionalization of the NHC ligands. This is depicted by the generation of the diphenylethylene-inserted isolable intermediate complex 4, from the reaction of 3a with diphenylacetylene in a 1:1 ratio, which eventually provides an annulated salt 5a-Br via reductive elimination. Gratifyingly, this process can also be made catalytic, which directly provides several mono-/bis-annulated cationic N-heterocyclic compounds starting from the imidazolium salts [(2a,b)-H]Br using [Ru(p-cymene)Cl2]2 as a precatalyst. Furthermore, subtle variations in the electronic profiles of the complexes 3a?c in combination with steric alterations are observed to influence their activity in the transfer hydrogenation of acetophenone, a model for the hydride transfer process. Among all the complexes studied here, complex 3b with an ImNHC donor at the second position of the naphthyl ring was identified as a superior catalyst in comparison to 3a,c featuring either a different NHC donor or substitution pattern with a low loading of 0.1 mol%.
- Bauri, Somnath,Mallik, Anirban,Rit, Arnab
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p. 3362 - 3374
(2020/10/02)
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- Heteroditopic Ru(II)-And Ir(III)-NHC Complexes with Pendant 1,2,3-Triazole/Triazolylidene Groups: Stereoelectronic Impact on Transfer Hydrogenation of Unsaturated Compounds
-
Imidazol-2-ylidene (ImNHC) and 1,2,3-Traizol-5-ylidene (tzNHC) have been established as important classes of carbene ligands in homogeneous catalysis. To develop Ru(II)/Ir(III) complexes based on these ligand systems considering their electronic as well as steric profiles for hydride transfer reactions, we employed chelating ligands featuring combinations of ImNHC and triazole-N or mesoionic tzNHC donors bridged by a CH2 spacer with possible modifications at triazole backbone. In general, synthesized Ru(II) complexes were found to perform significantly better than analogous Ir(III) complexes in ketone and aldimine reduction. Among the Ru(II) complexes, electron-rich complexes 8/9 of the general formula [(p-cymene)(ImNHC-CH2-TzNHC)RuII(Cl)]BF4 with two different carbene donors (ImNHC and tzNHC) were found to perform appreciably better in ketone reduction than analogous complexes with a combination of ImNHC and triazole-N-donor ([(p-cymene)(ImNHC-CH2-Tz-N)RuII(Cl)]BF4; 4) explaining the electronic fine-Tuning of the catalytic systems. No appreciable variation in activity was observed between complexes 8 and 9 having almost similar electronic profiles. However, less bulky Ru(II) complex 9 with a triazole N-phenyl substituent is more suitable for aldimine reduction than is complex 8, having a triazole N-3,5-dimethylphenyl substituent that explains the steric influence in addition to electronic effect on the reduction process.
- Illam, Praseetha Mathoor,Donthireddy,Chakrabartty, Sayantan,Rit, Arnab
-
supporting information
p. 2610 - 2623
(2019/07/31)
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- Synthesis of Benzylic Alcohols by C-H Oxidation
-
Selective methylene C-H oxidation for the synthesis of alcohols with a broad scope and functional group tolerance is challenging due to the high proclivity for further oxidation of alcohols to ketones. Here, we report the selective synthesis of benzylic alcohols employing bis(methanesulfonyl) peroxide as an oxidant. We attempt to provide a rationale for the selectivity for monooxygenation, which is distinct from previous work; a proton-coupled electron transfer mechanism (PCET) may account for the difference in reactivity. We envision that our method will be useful for applications in the discovery of drugs and agrochemicals.
- Tanwar, Lalita,B?rgel, Jonas,Ritter, Tobias
-
supporting information
p. 17983 - 17988
(2019/11/14)
-
- 3'-chlorobenzene propanol synthesis process
-
The invention relates to a 3'-chlorobenzene propanol synthesis process, which comprises the following concrete steps that 3'-chloropropiophenone and levo prolinol are sequentially added into 95-percent ethanol; after reaction liquid is completely dissolved, cooling is performed; potassium borohydride is added into reaction liquid in batches; heat insulation is performed after the addition is completed; after reaction liquid is subjected to heating and backflow reaction, the reaction liquid is subjected to pressure reduction concentration; n-hexane is added into the reaction liquid; heating isperformed; then, active carbon is added for heat insulation decoloration; reaction liquid is filtered; filter cake is eluted by the n-hexane; filter liquid is collected; the filter liquid is subjectedto crystallization and filtering; the filter cake is eluted by the n-hexane once; vacuum drying is performed to obtain the 3'-chlorobenzene. The final product of dextro 3'-chlorobenzene propanol is synthesized by using 3'-chloropropiophenone as a major raw material, using potassium borohydride as a reduction agent and using the levo prolinol as a catalyst. The produced 3'-chlorbenzene propanol isa dextro product; the crystallization temperature is higher than that of a mixed spinning product; the synthesis can be realized without needing a specific temperature reduction device; the energy consumption is reduced; the cost is reduced.
- -
-
Paragraph 0019; 0020; 0021
(2018/09/11)
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- Azetidine-Borane Complexes: Synthesis, Reactivity, and Stereoselective Functionalization
-
The present study reports, for the first time, the synthesis and structural features of azetidine-borane complexes, as well as their reactivity in lithiation reactions. A temperature-dependent stereoselectivity has been disclosed in the reaction of borane with N-alkyl-2-arylazetidines, allowing for a stereoselective preparation of azetidine-borane complexes 2 and 3. A regioselective hydrogen/lithium permutation, at the benzylic position, was observed in lithiation reactions of complexes possessing a syn relationship, between the ring proton and the BH3 group. In contrast, scarce or no reactivity was noticed in complexes lacking such a stereochemical requirement. The configurational stability of the lithiated intermediates has also been investigated, in order to shed some light on the stereoselectivity of the lithiation/electrophile trapping sequence. Calculations helped in supporting experimental observations, concerning structure and reactivity of these azetidine-borane complexes. Data suggest that the BH3 group could promote the lithiation reaction likely by an electrostatic complex induced proximity effect. Interestingly, a new synthetic strategy for the synthesis of N-alkyl-2,2-disubstituted azetidines has been developed.
- Andresini, Michael,De Angelis, Sonia,Uricchio, Antonella,Visaggio, Angelica,Romanazzi, Giuseppe,Ciriaco, Fulvio,Corriero, Nicola,Degennaro, Leonardo,Luisi, Renzo
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p. 10221 - 10230
(2018/08/01)
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- A Novel Phenylchromane Derivative Increases the Rate of Glucose Uptake in L6 Myotubes and Augments Insulin Secretion from Pancreatic Beta-Cells by Activating AMPK
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Purpose: A series of novel polycyclic aromatic compounds that augment the rate of glucose uptake in L6 myotubes and increase glucose-stimulated insulin secretion from beta-cells were synthesized. Designing these molecules, we have aimed at the two main pathogenic mechanisms of T2D, deficient insulin secretion and diminished glucose clearance. The ultimate purpose of this work was to create a novel antidiabetic drug candidate with bi-functional mode of action. Methods: All presented compounds were synthesized, and characterized in house. INS-1E cells and L6 myoblasts were used for the experiments. The rate of glucose uptake, mechanism of action, level of insulin secretion and the druggability of the lead compound were studied. Results: The lead compound (6-(1,3-dithiepan-2-yl)-2-phenylchromane), dose- and time-dependently at the low μM range increased the rate of glucose uptake in L6 myotubes and insulin secretion in INS-1E cells. The compound exerted its effects through the activation of the LKB1 (Liver Kinase B1)-AMPK pathway. In vitro metabolic parameters of this lead compound exhibited good druggability. Conclusions: We anticipate that bi-functionality (increased rate of glucose uptake and augmented insulin secretion) will allow the lead compound to be a starting point for the development of a novel class of antidiabetic drugs.
- Rozentul, Naomi,Avrahami, Yosef,Shubely, Moran,Levy, Laura,Munder, Anna,Cohen, Guy,Cerasi, Erol,Sasson, Shlomo,Gruzman, Arie
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p. 2873 - 2890
(2017/10/13)
-
- Effect of functional groups in organic chlorides on radical reduction with hydrostannane under microwave irradiation
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The effect of functional groups on the activation of molecules by microwave irradiation in the reduction of organic chlorides by Bu3SnH was investigated. The reactivity of a substrate with a hydroxy group increased under microwave heating conditions in comparison with conventional heating.
- Nishimoto, Yoshihiro,Yazawa, Satoshi,Kiyokawa, Kensuke,Kajiki, Takahito,Tsukahara, Yasunori,Yamauchi, Tomohisa,Wada, Yuji,Baba, Akio,Yasuda, Makoto
-
supporting information
p. 1116 - 1118
(2017/08/07)
-
- A hydrochloric acid west reaches anchors the sandbank preparation method (by machine translation)
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The invention discloses a method for preparing west reaches anchors the sandbank hydrochloride, including 3 - chlorobenzene propanol, 1 - phenyl - 3 - (1 - naphthoxy) - 1 - propanol, preparation of pure west reaches anchors the sandbank, west reaches anchors the sandbank DTTA salt preparation, preparation of west reaches anchors the sandbank, hydrochloric acid west reaches anchors the sandbank crude preparation and hydrochloric acid west reaches anchors the sandbank preparation of the finished product, the invention, accelerate the speed of production, the saving in material. (by machine translation)
- -
-
Paragraph 0041; 0042; 0043
(2017/08/29)
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- DOPAMINE D3 RECEPTOR ANTAGONISTS COMPOUNDS
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The disclosure is directed to novel dopamine D3 receptor antagonists, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, including treating drug dependency and psychosis.
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Page/Page column 325
(2016/05/19)
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- Sodium Bromide-Catalyzed Oxidation of Secondary Benzylic Alcohols Using Aqueous Hydrogen Peroxide as Terminal Oxidant
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A halide salt, hydroperoxide and AcOH catalyst system was applied to the oxidation of secondary benzylic alcohols. This simple system can be applied to a variety of secondary benzylic alcohols and scaled up for gram-scale preparation. High secondary benzylic alcohol selectivity of the present method is demonstrated in hydroxyketone synthesis. Based on several experimental results, a catalytic cycle for our oxidation is proposed.
- Komagawa, Hiromi,Maejima, Yukako,Nagano, Takashi
-
supporting information
p. 789 - 793
(2016/03/09)
-
- A combined computational and experimental investigation of the oxidative ring-opening of cyclic ethers by oxoammonium cations
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The propensity of oxoammonium cations to facilitate the oxidative ring-opening of cyclic ethers to their corresponding distal hydroxy ketones is investigated. The reaction has been evaluated using experimental and computational methods to gain deeper insight into trends in reactivity.
- Loman, Jacob. J.,Carnaghan, Emma R.,Hamlin, Trevor A.,Ovian, John M.,Kelly, Christopher B.,Mercadante, Michael A.,Leadbeater, Nicholas E.
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p. 3883 - 3888
(2016/05/24)
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- Synthesis of 3-Aryl-1-aminopropane Derivatives: Lithiation-Borylation-Ring-Opening of Azetidinium Ions
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In situ generated 2-phenyl-azetidinium ylides react with boronic esters to form acyclic γ-dimethylamino tertiary boronic esters. The transformation is believed to involve the formation of a zwitterionic boronate, which subsequently undergoes ring-opening 1,2-migration, which is promoted by the relief of ring strain. Owing to the configurational instability of the initially formed ylides, which appear to be in equilibrium with the open-chain carbene form, the reaction is not stereospecific. The C-B bond of the γ-dimethylamino tertiary boronic esters can be transformed into a variety of functional groups (C-OH, C-vinyl, C-H, C-BF3), thus giving a diverse selection of 3-aryl-1-aminopropanes, which represent a privileged motif among drug molecules.
- Casoni, Giorgia,Myers, Eddie L.,Aggarwal, Varinder K.
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p. 3241 - 3253
(2016/09/12)
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- Facile Protocol for Catalytic Frustrated Lewis Pair Hydrogenation and Reductive Deoxygenation of Ketones and Aldehydes
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A series of ketones and aldehydes are reduced in toluene under H2 in the presence of 5 mol % B(C6F5)3 and either cyclodextrin or molecular sieves affording a facile metal-free protocol for reduction to alcohols. Similar treatment of aryl ketones resulted in metal-free deoxygenation yielding aromatic hydrocarbons.
- Mahdi, Tayseer,Stephan, Douglas W.
-
supporting information
p. 8511 - 8514
(2015/11/27)
-
- Synthesis and in silico evaluation of novel compounds for PET-based investigations of the norepinephrine transporter
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Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylaminebased analogs of this compound. The newly synthesized compounds were computationally evaluated for their interactions with the monoamine transporters and represent reference compounds for PET-based investigation of the NET.
- Neudorfer, Catharina,Seddik, Amir,Shanab, Karem,Jurik, Andreas,Rami-Mark, Christina,Holzer, Wolfgang,Ecker, Gerhard,Mitterhauser, Markus,Wadsak, Wolfgang,Spreitzer, Helmut
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p. 1712 - 1730
(2015/01/30)
-
- Asymmetric hydrogenation of 3-chloro-1-phenylpropan-1-one catalyzed by ruthenium complexes
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Abstract A ruthenium complex modified with (1S,2S)-1,2-diphenyl-1,2-ethanediamine efficiently catalyzes asymmetric hydrogenation of 3-chloro-1-phenylpropan-1-one in the presence of potassium hydroxide solution in isopropyl alcohol, specific optical rotation of the synthesized products reaching -24.6°. Effects of the reaction time, hydrogen pressure, and the alkali concentration on the reaction course have been elucidated.
- Liu, Yanmei,Tai, Yulei,Guan, Ruqi,Chao, Guoku,Ye, Caiping,Li, Haihua,Li, Xiaoyan,Zhao, Yajuan
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p. 922 - 925
(2015/06/08)
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- Enantioselective reduction of propiophenone formed from 3-chloropropiophenone and stereoinversion of the resulting alcohols in selected yeast cultures
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Biotransformation of 3-chloro-1-phenylpropan-1-one 1 in sixteen selected cultures of yeast strains has been carried out. For most of the biocatalysts studied the substrate was fully consumed after 1-9 h of transformation, with the exception of the culture of Saccharomyces brasiliensis KCh 905, in which after 24 h trace amounts of the substrate were still visible (2%). However, apart from the expected enantiospecific reduction of the substrate to 3-chloro-1-phenylpropan-1-ol 3, the main biotransformation products comprised of a dehalogenation product - propiophenone 2 and the product of its reduction - 1-phenylpropan-1-ol 4. It was only in the cultures of five strains: Saccharomyces brasiliensis KCh 905, Rhodotorula marina KCh 77, Candida parapsilosis KCh 909, Candida viswanathii KCh 120, and Saccharomyces cerevisiae KCh 464 that 3-chloro-1-phenylpropan-1-ol 3 was observed in amounts of more than 10% of the product mixture. (S)-3-Chloro-1-phenylpropan-1-ol with ee = 91% was identified after 9 h of biotransformation in the culture of Candida viswanathii KCh 120, whereas (R)-3-chloro-1-phenylpropan-1-ol with ee = 28% was found in the culture of Aphanocladium album KCh 417. 1-Day biotransformation of propiophenone 2 in the cultures of Rhodotorula strains gave (S)-1-phenylpropan-1-ol 4 with a very high ee (95-99%) and 85-99% of substrate conversion, whereas transformation of this substrate in the cultures of Candida viswanathii KCh 120 and Candida parapsilosis KCh 909 led to (R)-1-phenylpropan-1-ol with ee = 98% and 97%, respectively. During biotransformation of propiophenone the percent composition of the reaction mixtures changed with time. Employment of the racemic mixture of 1-phenylpropan-1-ol 4 as a substrate for biotransformations allowed us to observe that the biocatalysts tested were capable of enantioselective oxidation of (S)-1-phenylpropan-1-ol. An exception was the culture of Rhodotorula glutinis KCh 242, in which after one day of biotransformation (S)-1-phenylpropan-1-ol was obtained with ee = 96%.
- Janeczko, Tomasz,Kostrzewa-Suslow, Edyta
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p. 1264 - 1269
(2015/01/16)
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- Chemoenzymatic synthesis of fluoxetine precursors. Reduction of β-substituted propiophenones
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Five endophytic yeast strains isolated from edible plants were tested in the reduction β-chloro- and β-azidopropiophenone for the preparation of optically active fluoxetine precursors. The biotransformation rendered not only the corresponding chiral γ-substituted alcohols, but also unsubstituted alcohols and ketones. The product profile was studied and a plausible mechanism for the reductive elimination of the β-functional group is proposed.
- Coronel, Camila,Arce, Gabriel,Iglesias, Cesar,Noguera, Cynthia Magallanes,Bonnecarrere, Paula Rodriguez,Giordano, Sonia Rodriguez,Gonzalez, David
-
-
- Bronsted acid catalyzed asymmetric SN2-Type O-alkylations
-
Bridging the gap: Bronsted acids catalyze an intramolecular S N2-type alkylation of alcohols with ethers by bridging a pentacoordinate transition state, thus simultaneously activating both the leaving group and nucleophile (see scheme). Density functional calculations provide detailed insight into the course of the reaction and the transition-state structure.
- Coric, Ilija,Kim, Ji Hye,Vlaar, Tjostil,Patil, Mahendra,Thiel, Walter,List, Benjamin
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supporting information
p. 3490 - 3493
(2013/05/09)
-
- Regioselective monochloro substitution in carbohydrates and non-sugar alcohols via Mitsunobu reaction: Applications in the synthesis of reboxetine
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A regioselective high yielding monochloro substitution (chlorohydrin formation) via Mitsunobu reaction is reported. In carbohydrates and sterically hindered non-sugars, only the primary hydroxyl group is chlorinated, whereas in the non-sugar 1,2- and 1,3-alcohols, predominantly the secondary chloride substitution occurs. The versatile methodology provides indirect access to epoxides with the retention of configuration, as against conventional Mitsunobu reaction which generates epoxides with inversion. The methodology was successfully used as a key step in the synthesis of optically active diastereoisomers of the antidepressant drug reboxetine from (R)-2,3-O- cyclohexylidene-d-glyceraldehyde in ～43% overall yields. The Royal Society of Chemistry.
- Dar, Abdul Rouf,Aga, Mushtaq A.,Kumar, Brijesh,Yousuf, Syed Khalid,Taneja, Subhash Chandra
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p. 6195 - 6207
(2013/09/12)
-
- Simplified heterocyclic analogues of fluoxetine inhibit inducible nitric oxide production in lipopolysaccharide-induced BV2 cells
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A series of fluoxetine, where the N-methylamino group was replaced and then simplified, were synthesized and their inhibitory effect was tested for nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-induced BV2 cells. Although the synthesized compounds generally revealed weaker activity or greater cytotoxicity than fluoxetine, compound 10a, in which the N-methylamino group in fluoxetine was replaced by morpholine, and the trifluoromethylphenyl ring was substituted with simple oxo group, suppressed NO production dose-dependently at 10, 20 and 40 μM concentrations with less cytotoxicity than fluoxetine, and inhibited iNOS mRNA and protein expression at the same concentrations in LPS-induced BV2 cells. The results suggested that the trifluoromethylphenyl ring moiety in fluoxetine is not necessary for the suppression of NO production and that 10a has the potential as a potent inhibitor of NO production.
- Park, Ju-Young,Kim, Seung-Woo,Lee, Ja-Kyeong,Im, Weon Bin,Jin, Byung Kwan,Yoon, Sung-Hwa
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experimental part
p. 538 - 544
(2012/02/15)
-
- Design, synthesis and evaluation of substituted N-(3-arylpropyl)-9,10- dihydro-9-oxoacridine-4-carboxamides as potent MDR reversal agents in cancer
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A novel class of molecules with structure N-(3-arylpropyl)-9,10-dihydro-9- oxoacridine-4-carboxamides (20-29) were designed by generating a pharmacophore for potent MDR reversal activity using phase drug design software. The designed molecules were synthesized by a novel synthesis route and evaluated for their inhibitory effects on the transport activity of P-glycoprotein (P-gp) by standard Hoechst 33342 assay method. Based on the pIC50 values of ten title compounds screened, three compounds exhibited better activity as compared to Verapamil used as standard.
- Velingkar,Dandekar
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experimental part
p. 504 - 510
(2012/01/06)
-
- Microwave-assisted synthesis and evaluation of substituted aryl propyl acridone-4-carboxamides as potential chemosensitizing agents for cancer
-
A novel class of compounds with structure Aryl propyl acridone-4- carboxamides were synthesized by conventional and microwave (MW) irradiation methods and evaluated for their inhibitory effects on the transport activity of P- glycoprotein (P-gp) by standard Hoechst 33342 assay method. The title compounds with phenoxy substitution exhibited better activity.
- Velingkar, Vinaykumar S.,Dandekar, Vikrant D.
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p. 268 - 275
(2013/01/10)
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- Preparation of fluoxetine by multiple flow processing steps
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Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.
- Ahmed-Omer, Batoul,Sanderson, Adam J.
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experimental part
p. 3854 - 3862
(2011/06/23)
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- Lipase-catalyzed synthesis of both enantiomers of 3-chloro-1-arylpropan-1- ols
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The lipase-catalyzed synthesis of both enantiomers of 3-chloro-1-(4- fluorophenyl)propan-1-ol, 3-chloro-1-(4-iodophenyl)propan-1-ol, and 3-chloro-1-phenylpropan-1-ol is described. The procedure is based on the enantiomer-selective acylation of the racemic alcohols in presence of lipase from Pseudomonas fluorescens (LAK) followed by the lipase from Candida rugosa (CRL) mediated hydrolysis of previously obtained enantiomerically enriched 1-aryl-3-chloropropyl esters. For the production of enantiopure (S)-1-aryl-3-chloropropan-1-ols (99% ee, 34-42% yield) the reactions were stopped at higher conversions than the theoretical optimum of 50%, while for enantiopure (R)-1-aryl-3-chloropropyl acetates (99% ee) the reactions were stopped at lower conversions. The latter compounds were enzymatically hydrolyzed into the corresponding (R)-1-aryl-3-chloropropan-1-ols (97-99% ee, 18-24% yield). The absolute configuration of the resolution products was determined by VCD measurements combined with quantum chemical calculations. Georg Thieme Verlag Stuttgart - New York.
- Pop, Laura Ancua,Czompa, Andrea,Paizs, Csaba,Toa, Monica Ioana,Vass, Elemer,Matyus, Peter,Irimie, Florin-Dan
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experimental part
p. 2921 - 2928
(2011/10/13)
-
- Design and synthesis of 3-(azol-1-yl)phenylpropanes as microbicidal spermicides for prophylactic contraception
-
We designed a series of 25 3-(azol-1-yl)phenylpropanes which yielded 10 compounds (3, 4, 7, 8, 13, 14, 19, 21, 23, 26) that irreversibly immobilized 100% human sperm at 1% (w/v) concentration in 60 s; 12 compounds (8, 9, 15, 16, 19-21, 23-25, 27, 28) that showed potent microbicidal activity at 12.5-50 μg/mL against Trichomonas vaginalis; and 17 compounds (3-11, 13, 15, 19, 21, 23, 26, 28, 30) that exhibited potent anticandida activity with minimum inhibitory concentration (MIC) of 12.5-50 μg/mL. Almost all the compounds exhibited high level of safety towards normal vaginal flora (Lactobacillus) and human cervical (HeLa) cells in comparison to the marketed spermicide nonoxynol-9 (N-9). All the biological activities were evaluated in vitro. Two compounds (4, 8) with good safety profile exhibited multiple (spermicidal, antitrichomonas and anticandida) activities, warranting further lead optimization for furnishing a prophylactic vaginal contraceptive.
- Kumar, Lalit,Sarswat, Amit,Lal, Nand,Jain, Ashish,Kumar, Sumit,Kiran Kumar,Maikhuri, Jagdamba P.,Pandey, Atindra K.,Shukla, Praveen K.,Gupta, Gopal,Sharma, Vishnu L.
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scheme or table
p. 176 - 181
(2011/02/27)
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- InCl3/Me3SiBr-catalyzed direct coupling between silyl ethers and enol acetates
-
A combined Lewis acid catalyst of InCl3 and Me3SiBr promoted the direct use of enol acetates in the coupling with low-reactive silyl ethers, in which functional groups including ketones and aldehydes survived. Sterically hindered silyl ethers such as ROSiEt3, ROSiPh3, ROSit-BuMe2, and ROSii-Pr3 were also applicable.
- Onishi, Yoshiharu,Nishimoto, Yoshihiro,Yasuda, Makoto,Baba, Akio
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supporting information; experimental part
p. 2762 - 2765
(2011/08/02)
-
- Direct oxidative installation of nitrooxy group at benzylic positions and its transformation into various functionalities
-
C-H Nitrooxylation at benzylic positions has been achieved by employing the N-hydroxyphthalimide (NHPI) catalyst/cerium(IV) ammonium nitrate (CAN) reagent system. The nitrooxy groups were demonstrated to function as tentative hydroxy protecting groups, as well as excellent leaving groups for N- and C-substitution reactions. Hence, the present method offers a unique way to synthesize diverse O-, N-, or C-functionalized benzylic compounds from simple alkyl aromatics.
- Kamijo, Shin,Amaoka, Yuuki,Inoue, Masayuki
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p. 4654 - 4657
(2011/09/30)
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- Enantioselective, ketoreductase-based entry into pharmaceutical building blocks: Ethanol as tunable nicotinamide reductant
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(Chemical Equation Presented) The use of NADH- and NADPH-dependent ketoreductases to access enantioenriched pharmaceutical building blocks is reported. Seven structurally diverse synthons are obtained, including those for atomoxetine (KRED 132), talampanel (RSt-ADH and CPADH), Dolastatin (KRED 132), and fluoxetine (KRED 108/132). Ethanol may be used as stoichiometric reductant, regenerating both nicotinamide cofactors, particularly under four-electron redox conditions. Its favorable thermodynamic and economic profile, coupled with its advantageous dual cosolvent role, suggests a new application for biomass-derived ethanol.
- Broussy, Sylvain,Cheloha, Ross W.,Berkowitz, David B.
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supporting information; experimental part
p. 305 - 308
(2009/07/18)
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- 1-[(3-Aryloxy-3-aryl)propyl]-1H-imidazoles, new imidazoles with potent activity against Candida albicans and dermatophytes. Synthesis, structure-activity relationship, and molecular modeling studies
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New 1-[(3-aryloxy-3-aryl)propyl]-1H-imidazoles were synthesized and evaluated against Candida albicans and dermatophytes in order to develop structure-activity relationships (SARs). Against C. albicans the new imidazoles showed minimal inhibitory concentrations (MICs) comparable to those of ketoconazole, miconazole, and econazole, and were more potent than fluconazole. Several derivatives (10, 12, 14, 18-20, 24, 28, 29, 30, and 34) turned out to be potent inhibitors of C. albicans strains resistant to fluconazole, with MIC values less than 10 μg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC ≤ 5 μg/mL) were equipotent to ketoconazole, econazole, and miconazole. SARs of imidazoles 10-44 were rationalized with reasonable accuracy by a previously developed quantitative pharmacophore for antifungal agents.
- La Regina, Giuseppe,D'Auria, Felicia Diodata,Tafi, Andrea,Piscitelli, Francesco,Olla, Stefania,Caporuscio, Fabiana,Nencioni, Lucia,Cirilli, Roberto,La Torre, Francesco,De Melo, Nadja Rodrigues,Kelly, Steven L.,Lamb, David C.,Artico, Marino,Botta, Maurizio,Palamara, Anna Teresa,Silvestri, Romano
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experimental part
p. 3841 - 3855
(2009/04/11)
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- PROCESS FOR PREPARING DAPOXETINE
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This invention relates to a new process for preparation of enantiomerically pure dapoxetine or an acid addition salt thereof i.e. S(+)-N,N-dimethyl-2-[2-(naphthalenyl oxy)ethyl]benzenemethanamine hydrochoride, a potent serotonin re-uptake inhibitor (SSRI), which comprises resolving racemic (±)-dapoxetine i.e. (±)- N,N-dimethyl-2-[2- (naphthalenyloxy)ethyl] benzene methanamine with a chiral acid so as to obtain salt of the chiral acid and (+)-dapoxetine, substantially free from (-)-dapoxetine.
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Page/Page column 8; 10
(2010/11/30)
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- 3-Amino-1-arylpropyl azaindoles and uses thereof
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The present invention provides compounds of the formula: or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein p, Ar, R1, R2, R3, Ra, Rb, Rc, Rd and Re are defined herein. Also provided are pharmaceutical compositions, methods of using, and methods of preparing the compounds.
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Page/Page column 39
(2008/06/13)
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- Synthesis and SAR studies of 3-phenoxypropyl piperidine analogues as ORL1 (NOP) receptor agonists
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A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified.
- Palin, Ronald,Barn, David R.,Clark, John K.,Cottney, Jean E.,Cowley, Phillip M.,Crockatt, Marc,Evans, Louise,Feilden, Helen,Goodwin, Richard R.,Griekspoor, Frank,Grove, Simon J.A.,Houghton, Andrea K.,Jones, Philip S.,Morphy, Richard J.,Smith, Alasdair R.C.,Sundaram, Hardy,Vrolijk, David,Weston, Mark A.,Wishart, Grant,Wren, Paul
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p. 589 - 593
(2007/10/03)
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- Imidazole analogues of fluoxetine, a novel class of anti-Candida agents
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Imidazole analogues of fluoxetine have been obtained by replacing the methylamino terminus of aminopropane chain with the imidazole ring. The newly designed imidazoles showed potent anti-Candida activity, superior to those of miconazole and other antifungal agents of clinical interest. 1-(4-Chlorophenyl)-l-(2,4-dichlorophenoxy)-3-(1H-imidazol-1-yl)propane (16), the most active among test imidazoles, Was about 2-fold more active and as much less cytotoxic than miconazole. High increase of activity was observed with methyl, nitro, fluorine, and chlorine (Cl > F > CH3 > NO2 > CF3).
- Silvestri, Romano,Artico, Marino,La Regina, Giuseppe,Di Pasquali, Alessandra,De Martino, Gabriella,D'Auria, Felicia Diodata,Nencioni, Lucia,Palamara, Anna Teresa
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p. 3924 - 3926
(2007/10/03)
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- [3H]-(R)-NPTS, a radioligand for the type 1 glycine transporter.
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The synthesis of NPTS, 6, a potent inhibitor of the type 1 glycine transporter (GlyT1) is described, as well as preparation of 6 in optically active and tritiated form for use as a radioligand for affinity displacement assay of GlyT1.
- Lowe 3rd., John A,Drozda, Susan E,Fisher, Katherine,Strick, Christine,Lebel, Lorraine,Schmidt, Christopher,Hiller, Donna,Zandi, Kathleen S
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p. 1291 - 1292
(2007/10/03)
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- Syntheses and Binding Studies of New [(Aryl)(aryloxy)methyl]piperidine Derivatives and Related Compounds as Potential Antidepressant Drugs with High Affinity for Serotonin (5-HT) and Norepinephrine (NE) Transporters
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In a wide search program toward new, efficient, and fast-acting antidepressant drugs, we have prepared series of new compounds having an (aryl)(aryloxy)methyl moiety linked directly or through a methylene chain to different substituted and unsubstituted cycles (isoquinoline, piperazine, piperidine, tetrahydropyran, or cyclopentane). These compounds have been evaluated for their affinities for serotonin (5-HT) transporter (SERT) and 5-HT1A and 5-HT2A receptors. Racemic mixtures of 4-[(aryl)(aryloxy)methyl]piperidine derivatives showed much higher affinity values for SERT than fluoxetine and resulted in lack of affinity for 5-HT 1A and 5-HT2A receptors. Some of these racemic mixtures were resolved to their enantiomers and tested for binding to norepinephrine (NE) transporter (NET), dopamine (DA) transporter (DAT), and α2 receptor. Several of these enantiomers [(-)-15b, (-)-15j, (-)-15t, (+)-15u] displayed a dual binding profile with affinities for SERT and NET with K i i = 1.9 and 13.5 nM, respectively), and further pharmacological characterization is in progress for its evaluation as a antidepressant.
- Orjales, Aurelio,Mosquera, Ramón,Toledo, Antonio,Pumar, M. Carmen,García, Neftalí,Cortizo, Lourdes,Labeaga, Luis,Innerárity, Ana
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p. 5512 - 5532
(2007/10/03)
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- Synthesis and preliminary biological characterization of a new potential 125I-radioligand for dopamine and serotonin receptors
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The synthesis and a preliminary biological characterization of a new class of N-benzyl-aminoalcohols which have serotonin (5-HT2) and dopamine (D2) receptor affinity is described. In vitro competition binding studies were conducted with the new molecules and 3H-spiperone on crude membrane preparation from rat striatum and frontal cortex. One of these compounds, 3-benzylamino-1-(4-fluoro-2-iodophenyl)-propan-1-ol (6f), whose IC50 values are in the micromolar range for both the D2 and 5-HT2 receptors, was prepared in iodine-125 labelled form (6i) by nucleophilic substitution of the bromine atom of 3-benzylamino-1-(2-bromo-4-fluorophenyl)-propan-1-ol (6d). In the in vivo studies, conducted on rats, the radiolabelled molecule 6i shows a good capacity to cross the blood-brain barrier (BBB) with a mean value of first pass cerebral extraction (E) of ca. 50% when the regional cerebral blood flow, measured with microsphere technique, is in the experimental animal's physiologic range (0.8-1 mL/min/g). A preliminary in vitro autoradiographic distribution on coronal rat brain slices of the radioiodinated molecule showed that it was preferentially localized in the striatum and in the cerebral regions rich in dopamine- and serotonin receptors, even if a high non-specific binding was observed.
- Guarna,Menchi,Berti,Cini,Bottoncetti,Raspanti,Politi,Pupi
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p. 3197 - 3206
(2007/10/03)
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- Identification and comparison of impurities in fluoxetine hydrochloride synthesized by seven different routes
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Fluoxetine HCl was prepared by seven different synthetic routes, all previously reported. The major impurities in each route were identified by GC/MS, HPLCMS, and gradient HPLC analysis. Impurities were classified as being derived from impurities in 4-chlorobenzotrifluoride, those arising during the SNAr reaction of this compound and 3-methylamino-1-phenyl-propanol, and those arising during the synthesis of this alcohol. Fifteen impurities belonging to the latter two categories were identified, and their structures were confirmed by synthesis of authentic material for most of the compounds. It was found that a variety of analytical tools was needed for complete characterization of the impurity profile of fluoxetine HCl and that purification of the intermediate and recrystallization of the drug itself are highly effective in minimizing the levels of the impurities.
- Wirth, David D.,Miller, Marybeth S.,Boini, Sathish K.,Koenig, Thomas M.
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p. 513 - 519
(2013/08/07)
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- Chemoenzymatic synthesis of the non-tricyclic antidepressants Fluoxetine, Tomoxetine and Nisoxetine
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3-Chloro-1-phenylpropan-1-ol and the corresponding butanoate, 3-chloro-1-phenyl-1-propyl butanoate, were kinetically resolved using lipase B from Candida antarctica catalysis by transesterification and hydrolysis respectively. The resulting chiral building blocks (S)- and (R)-3-chloro-1-phenylpropanol were converted into both enantiomers of the antidepressant drugs, Fluoxetine, Tomoxetine and Nisoxetine. The Royal Society of Chemistry 2000.
- Liu, Hui-Ling,Hoff, Bard Helge,Anthonsen, Thorleif
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p. 1767 - 1769
(2007/10/03)
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- Synthesis and characterization of fluorescent ligands for the norepinephrine transporter: Potential neuroblastoma imaging agents
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Radiolabeled m-iodobenzylguanidine (MIBG) is a tumor-seeking radioactive drug used in the diagnosis and treatment of pheochromocytomas and neuroblastomas. It is transported into the tumor cells by the neuronal norepinephrine (NE) transporter (NET) which is expressed in almost all neuroblastoma cells. Here, we describe the synthesis and some pharmacological properties of a series of fluorescent compounds structurally related to the NET substrate, MIBG, or to the NET inhibitors, (-)-(2R,3S)-cocaine and nisoxetine. Three of 10 synthesized fluorescent compounds, 1-(1- naphthylmethyl)guanidinium sulfate (1), 1-[2-(dibenz[b,f]azepin-5- yl)ethyl]guanidinium sulfate (2), and (2R,3S)-2β-ethoxycarbonyl-3β-tropanyl 5-(dimethylamino)naphthalene-1-sulfonate (6), exhibited high affinity (IC50 about 50 nM) for the NET. The nisoxetine derivatives 8 (rac-N-[(3- methylamino-1-phenyl)propyl]-5-(dimethylamino)-1-naphthalene-sulfonamide) and 9 (rac-4-[(3-methylamino-1-phenyl)propyl]amino-7-nitro-2,1,3-benzoxadiazole) and especially the guanidine derivative 4 (1-[4-(4-phenyl-l,3- butadienyl)benzyl]guanidinium sulfate) which are characterized by intermediate affinity for the NET (IC50 370-850 nM) caused significant and nisoxetine-sensitive cell fluorescence. At least the guanidine derivative 4 might represent a potentially useful agent for imaging of neuroblastoma cells.
- Hadrich, Dirk,Berthold, Frank,Steckhan, Eberhard,B?nisch, Heinz
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p. 3101 - 3108
(2007/10/03)
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- Reductive opening of phenyl substituted thiacycloalkanes: New way for sulphur-containing organolithium compounds
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The reaction of 2-phenyl substituted four, five and six membered thiacycloalkanes (1, 4 and 7) with lithium and a catalytic amount of DTBB (5 mol %) in THF at -78°C leads to the corresponding sulphur-containing benzylic organolithium compounds (2, 5 and 8), which by reaction with different electrophiles [D2O, Me3SiCl, Bu(t)CHO, Me2CO, Et2CO, (CH2)4CO, CO2] followed by hydrolysis with water afford the expected functionalised mercaptans (3, 6 and 9) in a regioselective manner. Some reaction products (3, 6) are cyclised under acidic conditions (85% phosphoric acid) to yield the corresponding homologous substituted sulphur-containing saturated heterocycles (10, 11).
- Almena, Juan,Foubelo, Francisco,Yus, Miguel
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p. 5563 - 5572
(2007/10/03)
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- 4,4'-Di-tert-butylbiphenyl-Catalysed Reductive Opening of Azetidines with Lithium: A Direct Preparation of 3,N-Dilithioalkylamines
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The reaction of N-phenylazetidine 1a with an excess of lithium powder and a catalytic amount of 4,4'-di-tert-butylbiphenyl (5 molpercent) in THF at -15 deg C leads to the corresponding dianion 2a, which by treatment with different electrophiles (H2O, D2O, ButCHO, PhCHO, (CH2)5CO, PhCH=NPh, CO2) yields, after hydrolysis with water, the expected functionalysed amines 3aa-ah.The same method applied to N-isopropyl-2-phenylazetidine 1c affords compounds 3ca-ce (electrophiles: H2O, D2O, PhCHO, Me2CO, CH2=CHCH2Br) resulting from the more stable benzylic intermediate 2c.Finally, the regiochemistry in the reductive opening of 2-methyl-N-phenylazetidine 1d followed by deuterolysis was studied: a mixture of both regioisomers 3da+3da' was obtained, the ratio being the oposite as expected according to the stability of both intermediates 2d and 2d'.
- Almena, Juan,Foubelo, Francisco,Yus, Miguel
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p. 5775 - 5782
(2007/10/02)
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- Behavior and extension of the scope of NADH models to the reduction of non-activated ketones by a stable indolo NADH model compound in the presence of Lewis acids
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The reduction of non-activated ketones, eg, acetophenone, by a very stable NADH model in the presence of Lewis acids (AlX3, Et2AlCl) is reported.During the reaction, a side equilibrated aldol condensation occurs.Due to the reversibility of this reaction, the overall yield in alcohol is not notably diminished.The scope of NADH models has been extended for the first time to non-activated ketones, such as dialkyl, aryl alkyl and diaryl ketones. - Keywords: NADH model / ketone reduction / Lewis acids / aldol condensation
- Berkous, Rabia,Dupas, Georges,Bourguignon, Jean,Queguiner, Guy
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p. 632 - 635
(2007/10/02)
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- N-Alkyl-3-phenyl-3-(2-halo-substituted phenoxy)Propylamines as norepinephrine uptake inhibitors
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This invention provides N-alkyl-3-phenyl-3-(2-substituted phenoxy)propylamines which are useful to treat neurological disorders associated with norepinephrine imbalance.
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- N-alkyl-3-phenyl-3-(2-substituted phenoxy) propylamines and pharmaceutical use thereof
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This invention provides N-alkyl-3-phenyl-3-(2-substituted phenoxy)propylamines which are useful to treat neurological disorders associated with norepinephrine imbalance.
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- An efficient route to enantiomerically pure antidepressants: Tomoxetine, nisoxetine and fluoxetine
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Both enantiomers (R)- and (S)-3-chloro-1-phenyl-1-propanol can be obtained conveniently by an efficient enzymatic resolution process. They can be converted via enantioconvergent routes into all enantiomers of the important antidepressants (R)- and (S)-Tomoxetine, Fluoxetine and Nisoxetine.
- Schneider,Goergens
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p. 525 - 528
(2007/10/02)
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- Aryloxyphenylpropylamines their preparation and use
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Novel aryloxyphenylpropylamines having the formula STR1 wherein X is H, cyano, halogen, halogenoalkyl, C1-6 -alkoxy, C1-6 -alkyl, C1-5 -alkanoyl, C3-5 -alkylene, aryloxy or aralkoxy, and R is 3,4-methylenedioxy, aryl or heteroaryl which are optionally substituted with one or more cyano, halogeno, C1-6 -alkyl, C1-6 -alkoxy, C1-6 -alkenyl, trifluoromethyl, C3-5 -alkylene, aryloxy or aralkoxy; and R1 and R2 independently is C1-10 -alkyl, C3-7 -cycloalkyl, C2-10 -alkenyl, C3-6 -cycloalkyl-C1-5 -alkyl, optionally substituted with C1-5 -alkoxy or cyano; R1 and R2 may together form a carbocyclic ring and a salt thereof with a pharmaceutically acceptable acid, provided however that R1 is not C3-7 -cycloalkyl, C1-10 -alkyl, or alkenyl which may be straight, branched or cyclic, unsubstituted or substituted with C1-4 -alkoxy, aryloxy or cycloalkyl or cycloalkylalkyl, when X is H and R2 is a methyl group. The novel compounds are useful in the treatment of anoxia, migraine, ischemia, epilepsy, traumatic injury and neurodegenerative diseases.
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- IMPROVED SYNTHESIS OF SUBSTITUTED OXETANES, TETRAHYDROFURANS, AND TETRAHYDROPYRANS FROM ω-CHLORINATED CARBOXYLIC ACID CHLORIDES
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The reaction of β-chloropropanoyl chloride (1) with a Grignard reagent leads to the corresponding 1,3-chlorohydrin (2), which by treatment with potassium hydride yields a substituted oxetane (4).The use of γ-chlorobutyryl chloride (7) in the same reaction following by refluxing in tetrahydrofuran permits the direct isolation of the corresponding tetrahydrofuran (8) in an one-pot process.Finally, by adding an organomagnesium reagent to δ-chloropentanoyl chloride (11) the corresponding 1,5-chlorohydrin (12) is isolated; the treatment of the latter systems with sodium hydride at tetrahydrofuran reflux leads to the expected substituted substituted tetrahydropyran (13).
- Barluenga, Jose,Rubiera, Covadonga,Fernandez, Jose R.,Florez, Josefa,Yus, Miguel
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p. 3242 - 3264
(2007/10/02)
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