14489-75-9Relevant articles and documents
New synthesis process of naftifine drug intermediate N-methyl-1-naphthalenemethylamine
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Paragraph 0024-0033, (2021/03/30)
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.
Simple RuCl3-catalyzed N-Methylation of Amines and Transfer Hydrogenation of Nitroarenes using Methanol
Sarki, Naina,Goyal, Vishakha,Tyagi, Nitin Kumar,Puttaswamy,Narani, Anand,Ray, Anjan,Natte, Kishore
, p. 1722 - 1729 (2021/04/19)
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.
Epoxide-Mediated Stevens Rearrangements of α-Amino-Acid-Derived Tertiary Allylic, Propargylic, and Benzylic Amines: Convenient Access to Polysubstituted Morpholin-2-ones
Jin, You-Xiang,Yu, Bang-Kui,Qin, Si-Ping,Tian, Shi-Kai
supporting information, p. 5169 - 5172 (2019/03/28)
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.
CYP2C19 and 3A4 Dominate Metabolic Clearance and Bioactivation of Terbinafine Based on Computational and Experimental Approaches
Davis, Mary A.,Barnette, Dustyn A.,Flynn, Noah R.,Pidugu, Anirudh S.,Swamidass, S. Joshua,Boysen, Gunnar,Miller, Grover P.
, p. 1151 - 1164 (2019/05/01)
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.
Selective synthesis of mono- and di-methylated amines using methanol and sodium azide as C1 and N1 sources
Chakrabarti, Kaushik,Mishra, Anju,Panja, Dibyajyoti,Paul, Bhaskar,Kundu, Sabuj
supporting information, p. 3339 - 3345 (2018/07/29)
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.
Synthetic method of naftifine drug intermediate N-methyl-1-naphthalene
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Paragraph 0014; 0015, (2016/11/21)
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.
Smooth isoindolinone formation from isopropyl carbamates via bischler-napieralski-type cyclization
Adachi, Satoshi,Onozuka, Masao,Yoshida, Yuko,Ide, Mitsuaki,Saikawa, Yoko,Nakata, Masaya
supporting information, p. 358 - 361 (2014/04/03)
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.
Selective monomethylation of primary amines with simple electrophiles
Lebleu, Thomas,Ma, Xiaolu,Maddaluno, Jacques,Legros, Julien
supporting information, p. 1836 - 1838 (2014/02/14)
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.
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
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
supporting information, p. 6671 - 6676,6 (2012/12/12)
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.
Highly enantioselective synthesis of tetrahydroquinolines via cobalt(II)-catalyzed tandem 1,5-hydride transfer/cyclization
Cao, Weidi,Liu, Xiaohua,Wang, Wentao,Lin, Lili,Feng, Xiaoming
supporting information; scheme or table, p. 600 - 603 (2011/04/15)
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.
