- New synthesis process of naftifine drug intermediate N-methyl-1-naphthalenemethylamine
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The invention discloses a new synthesis process of a naftifine drug intermediate N-methyl-1-naphthalenemethylamine. The process includes: adding phosphoric acid, concentrated hydrochloric acid, industrial naphthalene, paraformaldehyde and a catalyst, performing heating, introducing HCL gas, and carrying out reaction to obtain a 1-chloromethylnaphthalene crude product; performing cooling, dropwiseadding the 1-chloromethylnaphthalene crude product into a methanolamine solution, and carrying out reaction to obtain an N-methyl-1-naphthalenemethylamine crude product; performing evaporating to remove the redundant methanolamine solution, adjusting the alkali with a sodium hydroxide aqueous solution, conducting washing with water for layering, adding water and dichloromethane into an organic layer, adjusting the pH value with hydrochloric acid, performing layering, taking the water layer, and adjusting alkali with a sodium hydroxide solution to obtain a crude product, and carrying out reduced pressure rectification to obtain a finished product. According to the method, the N-methyl-1-naphthalenemethylamine finished product is successfully synthesized directly in a one-pot mode, the situation that the product yield is reduced due to the fact that a lot of residues are generated is avoided, meanwhile, the safety risk in the rectification process is avoided, the purity of the crude product is greatly improved, the cost is low, and the production safety is high.
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Paragraph 0024-0033
(2021/03/30)
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- Simple RuCl3-catalyzed N-Methylation of Amines and Transfer Hydrogenation of Nitroarenes using Methanol
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Methanol is a potential hydrogen source and C1 synthon, which finds interesting applications in both chemical synthesis and energy technologies. The effective utilization of this simple alcohol in organic synthesis is of central importance and attracts scientific interest. Herein, we report a clean and cost-competitive method with the use of methanol as both C1 synthon and H2 source for selective N-methylation of amines by employing relatively cheap RuCl3.xH2O as a ligand-free catalyst. This readily available catalyst tolerates various amines comprising electron-deficient and electron-donating groups and allows them to transform into corresponding N-methylated products in moderate to excellent yields. In addition, few marketed pharmaceutical agents (e. g., venlafaxine and imipramine) were also successfully synthesized via late-stage functionalization from readily available feedstock chemicals, highlighting synthetic value of this advanced N-methylation reaction. Using this platform, we also attempted tandem reactions with selected nitroarenes to convert them into corresponding N-methylated amines using MeOH under H2-free conditions including transfer hydrogenation of nitroarenes-to-anilines and prepared drug molecules (e. g., benzocaine and butamben) as well as key pharmaceutical intermediates. We further enable one-shot selective and green syntheses of 1-methylbenzimidazole using ortho-phenylenediamine (OPDA) and methanol as coupling partners.
- Sarki, Naina,Goyal, Vishakha,Tyagi, Nitin Kumar,Puttaswamy,Narani, Anand,Ray, Anjan,Natte, Kishore
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p. 1722 - 1729
(2021/04/19)
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- CYP2C19 and 3A4 Dominate Metabolic Clearance and Bioactivation of Terbinafine Based on Computational and Experimental Approaches
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Lamisil (terbinafine) is an effective, widely prescribed antifungal drug that causes rare idiosyncratic hepatotoxicity. The proposed toxic mechanism involves a reactive metabolite, 6,6-dimethyl-2-hepten-4-ynal (TBF-A), formed through three N-dealkylation pathways. We were the first to characterize them using in vitro studies with human liver microsomes and modeling approaches, yet knowledge of the individual enzymes catalyzing reactions remained unknown. Herein, we employed experimental and computational tools to assess terbinafine metabolism by specific cytochrome P450 isozymes. In vitro inhibitor phenotyping studies revealed six isozymes were involved in one or more N-dealkylation pathways. CYP2C19 and 3A4 contributed to all pathways, and so, we targeted them for steady-state analyses with recombinant isozymes. N-Dealkylation yielding TBF-A directly was catalyzed by CYP2C19 and 3A4 similarly. Nevertheless, CYP2C19 was more efficient than CYP3A4 at N-demethylation and other steps leading to TBF-A. Unlike microsomal reactions, N-denaphthylation was surprisingly efficient for CYP2C19 and 3A4, which was validated by controls. CYP2C19 was the most efficient among all reactions. Nonetheless, CYP3A4 was more selective at steps leading to TBF-A, making it more effective in terbinafine bioactivation based on metabolic split ratios for competing pathways. Model predictions did not extrapolate to quantitative kinetic constants, yet some results for CYP3A4 and CYP2C19 agreed qualitatively with preferred reaction steps and pathways. Clinical data on drug interactions support the CYP3A4 role in terbinafine metabolism, while CYP2C19 remains understudied. Taken together, knowledge of P450s responsible for terbinafine metabolism and TBF-A formation provides a foundation for investigating and mitigating the impact of P450 variations in toxic risks posed to patients.
- Davis, Mary A.,Barnette, Dustyn A.,Flynn, Noah R.,Pidugu, Anirudh S.,Swamidass, S. Joshua,Boysen, Gunnar,Miller, Grover P.
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p. 1151 - 1164
(2019/05/01)
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- Epoxide-Mediated Stevens Rearrangements of α-Amino-Acid-Derived Tertiary Allylic, Propargylic, and Benzylic Amines: Convenient Access to Polysubstituted Morpholin-2-ones
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A new strategy has been established for the synthesis of polysubstituted morpholin-2-ones through Stevens rearrangements of tertiary amines via in situ activation with epoxides. A range of α-amino acid-derived tertiary allylic, propargylic, and benzylic amines reacted with epoxides in the presence of zinc halide catalysts to afford structurally diverse allyl-, allenyl-, and benzyl-substituted morpholin-2-ones, respectively, in moderate-to-good yields with high regioselectivity. The process involves [2,3]- and [1,2]-Stevens rearrangements of quaternary ammonium ylide intermediates and constitutes a very convenient method to prepare polysubstituted morpholin-2-ones through tandem formation of C?N, C?O, and C?C bonds. Moreover, replacing epoxides with aziridines permitted the synthesis of polysubstituted piperazin-2-ones.
- Jin, You-Xiang,Yu, Bang-Kui,Qin, Si-Ping,Tian, Shi-Kai
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p. 5169 - 5172
(2019/03/28)
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- Selective synthesis of mono- and di-methylated amines using methanol and sodium azide as C1 and N1 sources
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A Ru(ii) complex mediated synthesis of various N,N-dimethyl and N-monomethyl amines from organic azides using methanol as a methylating agent is reported. This methodology was successfully applied for a one-pot reaction of bromide derivatives and sodium azide in methanol. Notably, by controlling the reaction time several N-monomethylated and N,N-dimethylated amines were synthesized selectively. The practical applicability of this tandem process was revealed by preparative scale reactions with different organic azides and synthesis of an anti-vertigo drug betahistine. Several kinetic experiments and DFT studies were carried out to understand the mechanism of this transformation.
- Chakrabarti, Kaushik,Mishra, Anju,Panja, Dibyajyoti,Paul, Bhaskar,Kundu, Sabuj
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supporting information
p. 3339 - 3345
(2018/07/29)
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- Synthetic method of naftifine drug intermediate N-methyl-1-naphthalene
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A synthetic method of naftifine drug intermediate N-methyl-1-naphthalene comprises steps as follows: 130 ml of propionitrile and 210 ml of methylamine are added to a reaction container provided with a stirrer, a thermometer, a condenser and a dropping funnel, the solution temperature is decreased to 13-16 DEG C, the stirring speed is controlled to range from 110 rpm to 130 rpm, 0.31 mol of amine methylnaphthalene is added slowly, the addition time is controlled within 3-4 h, the solution temperature is increased to 40-45 DEG C, the solution is left to stand for 30-36 h, the propionitrile is evaporated, 230 ml of cyclohexane is added to a remainder, the reminder is sequentially washed with a potassium bisulfite solution and a salt solution, dehydrated with a dehydrating agent and subjected to reduced pressure distillation, fractions at the temperature of 110-115 DEG C are collected and recrystallized in nitromethane, and N-methyl-1-naphthalene crystals are obtained, wherein the mass fraction of the propionitrile in Step (i) is 80%-85%, the cyclohexane 65%-70% and the potassium bisulfite solution 30%-35%, and the salt solution in Step (i) is any one of sodium bromite and potassium sulfate.
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Paragraph 0014; 0015
(2016/11/21)
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- Selective monomethylation of primary amines with simple electrophiles
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Direct monomethylation of primary amines with methyl triflate was achieved with high selectivity (up to 96%). The key point of this single methyl transfer stems from the use of HFIP as the solvent that interferes with amines and avoids overmethylation.
- Lebleu, Thomas,Ma, Xiaolu,Maddaluno, Jacques,Legros, Julien
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supporting information
p. 1836 - 1838
(2014/02/14)
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- Smooth isoindolinone formation from isopropyl carbamates via bischler-napieralski-type cyclization
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Isopropyl carbamates derived from benzylamines provide isoindolinones by treatment with phosphorus pentoxide at room temperature. Utility of this Bischler-Napieralski-type cyclization and a new mechanism involving a carbamoyl cation for rationalization of this smooth conversion are discussed.
- Adachi, Satoshi,Onozuka, Masao,Yoshida, Yuko,Ide, Mitsuaki,Saikawa, Yoko,Nakata, Masaya
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supporting information
p. 358 - 361
(2014/04/03)
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- Discovery of phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H- pyrimidin-2-one, an effective antithrombotic agent without associated bleeding and insulin resistance
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Structure-based evolution of the original fragment leads resulted in the identification of 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2- methylmorpholin-4-yl]-1H-pyrimidin-2-one, (S)-21, a potent, selective phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor with favourable in vivo antiplatelet effect. Despite its antiplatelet action, (S)-21 did not significantly increase bleeding time in dogs. Additionally, due to its enhanced selectivity over p110α, (S)-21 did not induce any insulin resistance in rats.
- Giordanetto, Fabrizio,Wallberg, Andreas,Ghosal, Saswati,Iliefski, Tommy,Cassel, Johan,Yuan, Zhong-Qing,Von Wachenfeldt, Henrik,Andersen, Soren M.,Inghardt, Tord,Tunek, Anders,Nylander, Sven
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supporting information
p. 6671 - 6676,6
(2012/12/12)
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- Highly enantioselective synthesis of tetrahydroquinolines via cobalt(II)-catalyzed tandem 1,5-hydride transfer/cyclization
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A chiral catalyst prepared from N,N′-dioxide and Co(BF 4)2·6H2O was applied in the asymmetric hydride transfer initiated cyclization reaction, giving optically active tetrahydroquinolines in good yields with high enantioselectivities under mild reaction conditions. Meanwhile, in light of the absolute configuration of the product, a possible working model was proposed to explain the origin of the activation and asymmetric induction.
- Cao, Weidi,Liu, Xiaohua,Wang, Wentao,Lin, Lili,Feng, Xiaoming
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p. 600 - 603
(2011/04/15)
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- Antimycobacterial activity of new 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-one derivatives. Molecular modeling investigations
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3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H37Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14α-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values.
- Zampieri, Daniele,Mamolo, Maria Grazia,Laurini, Erik,Fermeglia, Maurizio,Posocco, Paola,Pricl, Sabrina,Banfi, Elena,Scialino, Giuditta,Vio, Luciano
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experimental part
p. 4693 - 4707
(2009/10/24)
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- PREPARATION AND UTILITY OF SUBSTITUTED ALLYLAMINES
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Disclosed herein are substituted allylamines having structural Formula I, processes of preparation thereof, pharmaceutical compositions thereof, and the methods of their use thereof. (I)
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Page/Page column 64
(2008/12/06)
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- PROCESS FOR THE PREPARATION OF N-METHYL-1-NAPHTHALENEMETHANAMINE
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The present invention discloses an improved and impurity-free process for the preparation of N-methyl-1-naphthalenemethanamine of formula (I) starting from 1-chloromethylnaphthalene of formula (III). N-methylformamide is reacted with a strong base in N,N-dimethylformamide and/or non-polar solvent to get its anion and this anion is reacted with 1-chloromethylnaphthalene to get the formamide derivative of formula (VI). Alternatively, N-methylformamide (without generating the anion separately) and 1-chloromethylnaphthalene can be reacted together in the presence of a mild base and a phase transfer catalyst in N,N-dimethylformamide and/or a non-polar solvent to get the required formamide of formula (VI). The compound of formula (VI) on acid or base hydrolysis gave the required compound of formula (I). The main advantages of the present invention are it involves simple, economical, and easy to adopt process on a commercial scale. No tertiary-amine impurity is formed in this process. Compound of formula (I) is a key intermediate used in the synthesis of anti-fungal drug, terbinafine of formula (II).
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- HETEROCYCLIC COMPOUNDS, METHODS OF MAKING THEM AND THEIR USE IN THERAPY
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In part, the present invention is directed to antibacterial compounds of formula (I) wherein A is a bicyclic heteroaryl ring or a tricyclic ring and R2 is an heterocyclic residue; L is a bond, or L is alkyl, alkenyl or cycloalkyl.
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- Tuning saccharide selectivity in modular fluorescent sensors
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Five modular photoinduced electron-transfer (PET) sensors bearing two phenylboronic acid receptors with different fluorophores have been prepared. The sensors' interaction with saccharides was assessed via fluorescence spectroscopy. It was shown that monosaccharide selectivity is influenced by the choice of fluorescent moiety.
- Arimori, Susumu,Consiglio, Giuseppe A.,Phillips, Marcus D.,James, Tony D.
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p. 4789 - 4792
(2007/10/03)
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- Antifungal amine derivatives and processing for producing the same
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Novel amine derivatives having an excellent antimycotic effect represented by general formula (1) below and salts thereof are provided. [in the formula (1, R1represents a C1-5alkyl group which may be halogenated, R2represents 4-(1,1-dimethylalkyl)benzyl group, 4-(1-methyl-phenylethyl)benzyl group, 1-or 2-naphthylmethyl group, or a hydrocarbon group having 3,3-dimethyl-1-butynyl group or a phenyl group at its terminal and 1 to 3 double bonds; R3represents oxygen atom or a methylene group which may be substituted by a C1-4alkyl group; and R4represents 1-or 2 naphthyl group or a phenyl group which may be substituted.
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- Practical and efficient synthesis of C2 symmetrical diamines with Zn / Me3SiCl
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C2 symmetrical diamines are efficiently obtained by reductive coupling of imines with the couple Zn/Me3SiCl. This high yielding method is very practical and cheap for large scale preparation.
- Alexakis, Alexandre,Aujard, Isabelle,Mangeney, Pierre
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p. 873 - 874
(2007/10/03)
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- Antifungal composition
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A synergistically active antifungal composition comprising an azole compound and an arylmethylamine compound.
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- Highly selective TFAA-cleavage of tertiary 2,4-dimethoxybenzylamines and its use in the synthesis of secondary amines
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TFAA-treatment of allylic, propargylic, homopropargylic and some benzylic tert. 2, 4-dimethoxybenzylamines leads to highly selective cleavage of their dimethoxybenzylic C-N bonds. The resultant trifluoroacetamides can then readily be converted to the corresponding secondary amines.
- Nussbaumer,Baumann,Dechat,Harasek
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p. 4591 - 4602
(2007/10/02)
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- Synthesis and Structure-Activity Relationships of Naftifine-Related Allylamine Antimycotics
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Naftifine (1) is the first representative of the new antifungal allylamine derivatives.Its biological activity is strictly bound to specific structural requirements that are unrelated to those of known antifungals.A tertiary allylamine function seems to be a prerequisite for activity against fungi.By systematic variation of the individual structural elements in 1, detailed structure-activity relationships are defined in which the phenyl ring is the structural feature permitting the widest variations.Versatile synthetic routes to allylamine derivatives and comparative biological data are presented.
- Stuetz, Anton,Georgopoulos, Apostolos,Granitzer, Waltraud,Petranyi, Gabor,Berney, Daniel
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p. 112 - 125
(2007/10/02)
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- Trans-n-cinnamyl-n-methyl-(1-naphthylmethyl)amine
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Cinnamylalkyl-1-naphthylmethylamines, useful as antimycotic agents, and processes for their production.
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- Folate Antagonists. 18. Synthesis and Antimalarial Effects of N6-(Arylmethyl)-N6-methyl-2,4,6-pteridinetriamines and Related N6,N6-Disubstituted 2,4,6-Pteridinetriamines
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N6-(Arylmethyl)-N6-methyl-2,4,6-pteridinetriamines (1-5) and related N6-substituted 2,4,6-pteridinetriamines (16-20) were obtained by the condensation of 6-chloro-2,4-pteridinediamine with methylarylmethanamine and other selected secondary amines.The requisite N-methylarylmethanamines (21-32) were prepared by the hydrogenation over Pt/C of the corresponding arylcarboxaldehyde in the presence of methanamine.Several of the N6-(arylmethyl)-N6-methyl-2,4,6-pteridinetriamines exhibited exceptional suppressive antimalarial activity against a drug-sensitive line of Plasmodium berghei in mice.N6-Methyl-N6-(1-naphthalenylmethyl)-2,4,6-pteridinetriamine (9), the most active of those compounds, was also shown to be curative at 3.16 mg/kg in a single oral dose against P. cynomolgi in the rhesus monkey.This compound was also shown to be effective against a chloroquine-resistant line of P. berghei in the mouse but showed cross-resistance to a pyrimethamine-resistant strain.Most of the 2,4,6-pteridinetriamines showed strong antibacterial action against Streptococcus faecalis and Staphylococcus aureus.
- Elslager, Edward F.,Johnson, Judith L.,Werbel, Leslie M.
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p. 140 - 145
(2007/10/02)
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