- Converging and Diverging Synthetic Strategies to Tetradentate (N,N')-Diaminomethyl,(P,P')-Ferrocenyl Ligands: Influence of tert-Butyl Groups on Ferrocene Backbone Conformation
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Hexasubstituted hybrid tetradentate (N,N',P,P')-ferrocenes bearing phosphino and aminomethyl groups, plus hindering tert-butyl moieties, were synthesized by using two different strategies: a "diverging" synthesis involving successive functionalization of preformed di-tert-butylated ferrocene and a "converging" assembly of the species from appropriately substituted cyclopentadienyl rings. While the new cyclopentadienyl salts formed are of interest, their assembly with iron dichloride used as a "converging" way to produce tetradentate ferrocene ligands presented several drawbacks. Conversely, the synthesis of new tert-butylated (aminomethyl)ferrocene derivatives was found convenient to further form (N,N')-aminomethyl,(P,P')-tert-butylated-ferrocenyl diphosphines by N-directed ortho-metalation. The novel N2-didentate and N2P2-tetradentate tert-butylated ferrocene compounds were all synthesized in good to high yields (48-96%) and tolerated aryl, alkyl, and heteroaryl phosphino groups as substituents on nitrogen and phosphorus atoms. They were characterized by X-ray diffraction and multinuclear NMR (1H, 13C, 31P, 15N). We observed the conformation control provided to rac-(N,N')-diaminomethyl-(P,P')-tert-butylated-ferrocenyldiphosphines with in particular the systematic near-eclipsed conformation of aminomethyl groups. This conformation is at the origin of the unexpected formation at RT of a zwitterionic cyclopalladate from an (aminomethyl)ferrocene derivative, arising from intramolecular Cp-proton transfer to the proximate free amino group by simple C-H activation reaction in the presence of palladium dichloride.
- Allouch, Fatima,Dwadnia, Nejib,Vologdin, Nikolay V.,Svyaschenko, Yurii V.,Cattey, Hélène,Penouilh, Marie-José,Roger, Julien,Naoufal, Daoud,Ben Salem, Ridha,Pirio, Nadine,Hierso, Jean-Cyrille
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Read Online
- PROCESSES FOR PREPARING A MDM2 INHIBITOR
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The present invention provides commercial processes for preparing 2- ((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-l-((S)-l-(isopropylsulfonyl)-3-methylbutan-2-yl)-3 -m ethyl-2-oxopiperi din-3 -yl)acetic acid as well as intermediates thereof.
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Paragraph 0119; 0135; 0136
(2020/03/23)
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- Practical Synthetic Method for the Preparation of Pyrone Diesters: An Efficient Synthetic Route for the Synthesis of Dolutegravir Sodium
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A highly efficient and practical synthetic method for the preparation of pyrone diesters was established. The pyrone diester 3c can be prepared from readily available starting materials on a multihundred gram scale. The pyrone diester 3c can easily be converted to dolutegravir sodium (1). The synthetic route demonstrated herein provides an efficient and atom-economical synthetic method for preparing this potent anti-HIV agent.
- Yasukata, Tatsuro,Masui, Moriyasu,Ikarashi, Fumiya,Okamoto, Kazuya,Kurita, Takanori,Nagai, Masahiko,Sugata, Yoshihide,Miyake, Naoki,Hara, Shinichiro,Adachi, You,Sumino, Yukihito
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p. 565 - 570
(2019/03/26)
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- Synthetic method of diethyl dimethylaminomethylenemalonate
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The invention belongs to the technical field of chemical synthesis, and concretely relates to a synthetic method of diethyl dimethylaminomethylenemalonate. The synthetic method provided by the invention includes the following steps: (1) reacting a compound I with a compound II at 70-90 DEG C to obtain a compound III; and (2) reacting the compound III and a compound IV with organic solvents at 20-30 DEG C in the presence of a catalyst and organic bases to obtain a compound V. The synthetic method of the invention is high in product yield, low in production cost, simplified in post-treatment operation, energy saving, environmentally friendly, and easy in large-scale production. The concrete synthetic route is shown in the description.
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Paragraph 0024; 0025; 0026; 0027
(2019/05/08)
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- Preparation method of enamine compounds
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The invention relates to the field of preparation of enamine compounds, and discloses a preparation method of the enamine compounds shown in a formula (I). The method comprises the step of enabling acompound as shown in a formula (II) to react with a compound as shown in a formula (III) in presence of an alkaline substance; the formula (I), the formula (II) and formula (III) are described in thedescription, wherein R1 is hydrogen or alkyl groups of C1-C4; R2, R3 and R4 are the same or different and are independently the alkyl groups of C1-C4; n is 0 or 1. The preparation method is simpler and more convenient in process, easy in obtaining of raw materials, lower in cost, and high in reaction conversion rate and selectivity.
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Paragraph 0037-0041
(2019/10/15)
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- Preparation method of azoxystrobin intermediate
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The invention relates to a preparation method of an azoxystrobin intermediate. According to the method, a compound shown in a formula (II) serves as a raw material and reacts with a methylating agentunder a basic condition to obtain the azoxystrobin intermediate shown in a formula (I), wherein Z1 represents halogen. The method has the advantages that the reaction time is short, the total yield ishigh, the cost of raw materials is low, and the method is suitable for large-scale production and has very important significance for industrial production of final products of azoxystrobin. The formula (II) and the formula (I) are shown in the description.
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Paragraph 0036; 0037; 0038
(2018/09/29)
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- Increasing global access to the high-volume HIV drug nevirapine through process intensification
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Access to affordable medications continues to be one of the most pressing issues for the treatment of disease in developing countries. For many drugs, synthesis of the active pharmaceutical ingredient (API) represents the most financially important and technically demanding element of pharmaceutical operations. Furthermore, the environmental impact of API processing has been well documented and is an area of continuing interest in green chemical operations. To improve drug access and affordability, we have developed a series of core principles that can be applied to a specific API, yielding dramatic improvements in chemical efficiency. We applied these principles to nevirapine, the first non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV. The resulting ultra-efficient (91% isolated yield) and highly-consolidated (4 unit operations) route has been successfully developed and implemented through partnerships with philanthropic entities, increasing access to this essential medication. We anticipate an even broader global health impact when applying this model to other active ingredients.
- Verghese, Jenson,Kong, Caleb J.,Rivalti, Daniel,Yu, Eric C.,Krack, Rudy,Alcázar, Jesus,Manley, Julie B.,McQuade, D. Tyler,Ahmad, Saeed,Belecki, Katherine,Gupton, B. Frank
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supporting information
p. 2986 - 2991
(2017/07/24)
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- A Bench-Stable Vilsmeier Reagent for in situ Alcohol Activation: Synthetic Application in the Synthesis of 2-Amino-2-Thiazolines
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A robust, chemoselective direct condensation/cyclization of thioureas and amino alcohols is described. Employing a bench-stable Vilsmeier reagent, methoxymethylene- N, N -dimethyliminium methyl sulfate, the selective in situ activation of alcohols is achieved with high efficiency and broad functional-group tolerance. The reversible interaction of the Vilsmeier reagent with substrate was key to the success of this activation strategy.
- Corbett, Michael T.,Caille, Seb
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supporting information
p. 2845 - 2850
(2017/10/06)
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- Synthesis method of 3-amino-5-N,N-dimethyl pyrazole
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The invention relates to a synthesis method of 3-amino-5-N,N-dimethyl pyrazole, and belongs to the field of chemical synthesis. Aiming at problems that when amino-containing pyrazole compounds are prepared by a conventional one-pot method, the yield and the activity of the compounds are low, and the synthesized products are liable to decompose when affected by the environment, the synthesis method comprises the steps of preparing N-methoxymethylene-N,N-dimethylmethanesulfonamide from methyl iodide and dimethylformamide, preparing sodium cyanoacetate from cyanoacetic acid and sodium hydroxide, and then preparing N,N-dimethylaminoacrylonitrile by mixing N-methoxymethylene-N,N-dimethylmethanesulfonamide and sodium cyanoacetate, and then by conducting a reaction between N,N-dimethylaminoacrylonitrile and hydrazine hydrate, 3-amino-5-N,N-dimethyl pyrazole is obtained. By adopting a two-step method for preparing 3-amino-5-N,N-dimethylpyrazole, the yield of the N, N-dimethyl pyrazole compound is increased to 75-80%.
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Paragraph 0008; 0009; 0010
(2017/08/28)
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- LOWCOST, HIGH YIELD SYNTHESIS OF NEVIRAPINE
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Improved methods of producing the HIV drug substance, nevirapine are provided. The methods employ a cost effective and high yield synthetic methods for preparing the nevirapine building block 2-chloro-3-amino-4-picoline (CAPIC) and 2-cyclopropyl amino nicotinate (Me-CAN), and improvements in other steps of nevirapine synthesis.
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Page/Page column 22; 23
(2016/12/22)
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- Novel process for preparing 4,4-difluoro-((2-dialkylamino) methylene)-3-oxobutanic acid alkyl ester
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The present invention relates to a novel method for preparing 4,4-difluoro-((2-dialkylamino) methylene)-3-oxobutanic acid alkyl ester which is represented by the following chemical formula ( I ) and useful as a manufacturing intermediate for fungicides such as isopyrazam, sedaxane, bixafen and the like. In the formula ( I ), R 1 and R 2 are each a C 1 to C 4 alkyl group, and R is a methyl group or an ethyl group. The compound of the formula ( I ) is produced by reacting dialkylformamide dialkyl acetal with a difluoro ketoester.
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Paragraph 0051; 0052
(2017/01/31)
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- N '-aryl-N, N-dimethyl-formamidine new method for the preparation of (by machine translation)
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The present invention provides a synthetic N '-aryl-N, N-dimethyl-formamidine of the new method. The method firstly to N, N-dimethyl formamide and dimethyl sulfate to imine salt; generating imide salt in the presence of an alkali, and aromatic amine reaction generating N '-aryl-N, N-dimethyl-carboximidamide; the amidines same with other amine function generating [...] compound, can be used in the anti-tumor drug AKT, synthesis of lapatinib and gefitinib, and the like. Mild reaction conditions of the method, is suitable for industrial production. (by machine translation)
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Paragraph 0031; 0032
(2017/02/17)
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- Bicyclo[6.3.0]undecapentaenyl anion: The next higher homolog of the indenyl anion with exceptionally large ion-pairing effects on its tropicity
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The title anion 1 was generated as a fairly thermally stable species in tetrahydrofuran (THF) and dimethylsulfoxide (DMSO) by the action of several bases (sodium hydride, potassium hydride, lithium diisopropylamide, and lithium hexamethyldisilazide) with appropriate bicyclo[6.3.0]undecapentaenes. Variable-temperature 1H NMR spectra of 1×Li+ in [D8]THF reveal that the anion exhibits exceptionally large ion-pairing effects; proton chemical shifts vary by more than 1 ppm as a function of ion-pairing conditions. Thus, anion 1, in a contact ion pair (Li+ at ambient temperature in THF), behaves as an aromatic cyclopentadienyl anion that is perturbed only slightly by the electronic effects of a paramagnetic cyclooctatetraene (COT), whereas 1 in a separated ion pair (Li+ at low temperatures in THF or at ambient temperature in DMSO) behaves as an overall paratropic species with a 12 π-electron periphery. 13C NMR spectroscopy indicates no major skeletal rearrangement and only small variations of the electron density. The variable tropicity of 1 can be ascribed to small conformational changes of the molecule. In addition to its unusual, tunable tropicity, anion 1 can also serve as a versatile building block for the synthesis of cyclopentanoid conjugated systems fused to a fully unsaturated eight-membered ring. A theoretical calculation predicts that the 10-position of 1 should have the highest electron density. In agreement with this prediction, the reactions of 1 with electrophiles occur predominantly at the 10-position. The corresponding ferrocene, two fulvenes, two diazo derivatives, and a COT-fused azulene were obtained by the reactions of 1 with appropriate electrophiles. Split personality: The bicyclo[6.3.0]undecapentaenyl anion, which is the next higher homolog of the indenyl anion, behaves as an aromatic cyclopentadienide ion slightly perturbed by the effects of a paramagnetic cyclooctatetraene in a contact ion pair, whereas in a solvent-separated ion pair it is an overall paratropic species owing to a 12 π-electron periphery (see picture). Copyright
- Ozoe, Hiroaki,Uno, Yasutaka,Kitamura, Chitoshi,Kurata, Hiroyuki,Oda, Masaji,Jones Jr., John W.,Scott, Lawrence T.,Kawase, Takeshi
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p. 893 - 900
(2014/03/21)
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- PROCESS FOR THE PREPARATION OF 3-HALOALKYLPYRAZOLES
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The present invention provides a process for the preparation of a compound of formula (I) wherein R1 is C1-C4 haloalkyl; R2 is optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl; and R3 is methyl or ethyl; comprising reacting a compound of formula (IV) wherein R1, R2 and R3 are as defined for the compound of formula I; with an alkylating agent in the presence of an amide.
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Page/Page column 20
(2012/03/09)
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- Development of two scalable syntheses of 4-amino-5-aminomethyl-2- methylpyrimidine: Key intermediate for vitamin b1
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Two scalable processes for the synthesis of 4-amino-5-aminomethyl-2- methylpyrimidine (2) are described. In the first approach, the less expensive 2-cyanoacetamide was reacted with Vilsmeier reagent to afford enamine 18, followed by the condensation with acetamidine to produce the 4-amino-2-methylpyrimidine-5-carbonitrile (6); subsequent hydrogenation gave 2 in 65% overall yield. In the second approach, malononitrile was treated with the ionic salt 21, prepared in situ from DMF and dimethyl sulfate, to give 18, which, without isolation was reacted with acetamidine hydrochloride to afford the common intermediate 6. Overall yield of this approach was 70%. Both methods are performed in a convenient manner suitable for industrial use.
- Zhao, Lei,Ma, Xiao-Dong,Chen, Fen-Er
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experimental part
p. 57 - 60
(2012/05/31)
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- [2 + 2] Annulation of aldimines with sulfonic acids: A novel one-pot cis-selective route to β-sultams
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A novel DMF/dimethyl sulfate promoted [2 + 2] annulation of aldimines with sulfonic acids afforded β-sultams in good to excellent yields (35-93%) under mild conditions. The protocol offers a convenient alternative to highly corrosive and hygroscopic sulfo
- Rai, Ankita,Rai, Vijai K.,Singh, Atul K.,Yadav, Lal Dhar S.
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experimental part
p. 4302 - 4306
(2011/09/16)
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- Efficient one-pot synthesis of 2-azetidinones from acetic acid derivatives and imines using methoxymethylene-N,N-dimethyliminium salt
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A cheap, versatile and convenient method for synthesis of β-lactams using methoxymethylene-N,N-dimethyliminium salt as an acid activator in Staudinger reaction is reported. This method is used for the preparation of monocyclic, spirocyclic, N-alkyl and th
- Jarrahpour, Aliasghar,Zarei, Maaroof
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experimental part
p. 5017 - 5023
(2010/08/19)
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- DMF-dimethyl sulfate as a new reagent for the synthesis of β-lactams
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A number of 2-azetidinones were synthesized in good to excellent yields by a novel reaction between Schiff bases, substituted acetic acids and alkoxymethylene-N,N-dimethyliminium salts, the adduct formed from DMF and O-alkylating agents. The advantages of
- Jarrahpour, Aliasghar,Zarei, Maaroof
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experimental part
p. 1568 - 1570
(2009/06/28)
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- Tautomerism in the solid state and in solution of a series of 6-aminofulvene-1-aldimines
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To study systems able to sustain intramolecular proton-transfer, we have prepared a series of six aminofulvene aldimines including several labeled with 15N and 2H. These compounds show coupling constants through the hydrogen bond, 1hJ(15N-1H) and 2hJ(15N-15N). The position of the tautomeric equilibria, i.e., on what nitrogen atom is the proton, was determined in the solid state and in solution. The crystal structure of N{([5-[(phenylamino)methylene]- 1,3-cyclopentadien-1-yl]methylene})pyrrole-1-amine (3) has been determined by X-ray analysis. In solution, both N-H and C-H tautomers were observed and their structures assigned by NMR spectroscopy. Particularly useful is the value of the 1J(15N-1H) coupling constant.
- Sanz, Dionisia,Perez-Torralba, Marta,Alarcon, Sergio Hugo,Claramunt, Rosa Maria,Foces-Foces, Concepcion,Elguero, Jose
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p. 1462 - 1471
(2007/10/03)
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- Generation and in Situ Acylation of Enaminone Anions: A Convenient Synthesis of 3-Carbethoxy-4(1H)-pyridinones and -4-pyrones and Related Compounds
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Treatment of 2--3-oxobutanoates 9 or 10 with LiN(SiMe3)2 in the presence of RCOCl results in C-acylation.The resulting intermediate, without isolation, may be converted to 6-R 3-Carbethoxy-4-pyrones (e.g., 12) by H3O+ or to the corresponding pyridinones (e.g., 13) by NH4OAc.Typically, yields are 55-75percent for R groups lacking acidic α or γ protons and ca. 30percent for R = Me2CH or MeCH=CH.Replacing 9 with MeCOC(=CHNMe2)SCH2Ph (from MeCOCH2SCH2Ph and Me2NCH(OMe)2 similarly affords 3-(PhCH2S)-substituted products such as 29.Alkylation of the pyridinone anions produces mixtures of N- and O-substituted compounds, with the latter predominating; aminolysis of the isolated pyrones (R'NH2-HOAc, where R' = alkyl, Ar, HO, etc.) is the preferred route to the 1-R'-substituted pyridinones.
- McCombie, Stuart W.,Metz, William A.,Nazareno, Dennis,Shankar, Bandarpalle B.,Tagat, Jayaram
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p. 4963 - 4967
(2007/10/02)
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- Synthesis and Properties of Vinylogous 6-(Cyclopentadienyl)pentafulvenes
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The application of the principle of kinetic stabilization on vinylogous 6-(cyclopentadienyl)pentafulvenes 1 led to the synthesis of the di- and tetra-tert-butyl derivatives 7a-e and 8a-c.Their reactions with bases and acids form charged, heteroatom-free cyanine-type carbanionic 9a-e, 10a-c and carbocationic 11a-e, 12a-c species which were characterized with NMR and UV/Vis spectroscopy.Conclusions on the ion pair structures of the alkali metal salts 9a-e and 10a-c are drawn from the spectroscopic data.Additionally, in one case the behavior of the alkali metal salt 10b towards oxidants was studied by cyclic voltammetry and the structure of the corresponding hydrocarbon 8b was proved by X-ray structural analysis.
- Eiermann, Matthias,Stowasser, Bernd,Hafner, Klaus,Bierwirth, Klaus,Frank, Anette,et al.
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p. 1421 - 1431
(2007/10/02)
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- Reaction of Singlet Oxygen with Enamino Carbonyl Systems. A General Method for the Synthesis of α-Keto Derivatives of Lactones, Esters, Amides, Lactams, and Ketones
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A general method for the introduction of a ketone α to the carbonyl group of a ketone, lactone. ester, substituted amide, or lactam has been developed involving the formation and dye-sensitized photooxygenation of enamino carbonyl intermediates.
- Wasserman, Harry H.,Ives, Jeffrey L.
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p. 3573 - 3580
(2007/10/02)
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