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Usage

Uses

4-Fluoro-n-methylbenzylamine

InChI:InChI=1/C8H10FN/c1-10-6-7-2-4-8(9)5-3-7/h2-5,10H,6H2,1H3/p+1

Upstream product

• 459-46-1 4-Fluorobenzyl bromide 
• 74-89-5 methylamine 
• 84174-25-4 p-fluorobenzylamine formamide 
• 352-11-4 1-chloromethyl-4-fluorobenzene 
• 593-51-1 methylamine hydrochloride 
• 459-57-4 4-fluorobenzaldehyde 
• 104156-56-1 1-(4-fluorophenyl)-N-methylmethanimine 
• 167300-01-8 tert-butyl N-(4-fluorobenzyl)-N-methylcarbamate 
• 153903-23-2 (4-fluorobenzyl)carbamic acid tert-butyl ester 
• 140-75-0 para-fluorobenzylamine 
• 333-27-7 methyl trifluoromethanesulfonate 
• 124-38-9 carbon dioxide 
• 67-56-1 methanol 
• 159979-96-1 4-fluorobenzyl azide 

Downstream Products

• 368-06-9 (2-fluoro-benzyl)-(4-fluoro-benzyl)-methyl-amine 
• 128667-26-5 6-{3-[(4-Fluoro-benzyl)-methyl-amino]-2-hydroxy-propoxy}-1H-quinolin-2-one 
• 84174-21-0 N-(4-fluorobenzyl)-N-methylnitrous amide 
• 1027887-38-2 N-(4-Fluoro-benzyl)-N-methyl-2-(4-nitro-phenoxy)-acetamide 
• 863492-49-3 (S)-{[(4-fluorobenzyl)methylcarbamoyl]phenyl-methyl}carbamic acid tert-butyl ester 
• 871936-97-9 3-benzyloxy-2-[4-fluorobenzyl(methyl)aminocarbonyl]-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 
• 933759-96-7 C₁₁H₁₇FN₂ 
• 957113-04-1 C₃₄H₄₃F₂N₃O₆ 
• 1053173-94-6 4R-(4-benzyloxy-phenyl)-3-(4-fluorophenyl)-2-oxo-oxazolidine-5S-carboxylic acid (4-fluorobenzyl)methylamide 
• 1033443-41-2 3-cyclopentyl-5-((4-fluorobenzyl)(methyl)amino)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one 
• 1174903-51-5 3-[[(4-fluorobenzyl)-methyl-amino]methyl]-5-(pyridin-4-yl)-1,3,4-oxadiazol-2(3H)-one 
• 1194045-77-6 C₁₈H₂₅FN₂O₃ 
• 1232682-42-6 C₁₅H₁₆FNO₄ 

Relevant academic research and scientific papers

Selective synthesis of mono- and di-methylated amines using methanol and sodium azide as C1 and N1 sources

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.

Selective Monomethylation of Amines with Methanol as the C1 Source

The N-monomethyl functionality is a common motif in a variety of synthetic and natural compounds. However, facile access to such compounds remains a fundamental challenge in organic synthesis owing to selectivity issues caused by overmethylation. To address this issue, we have developed a method for the selective, catalytic monomethylation of various structurally and functionally diverse amines, including typically problematic primary aliphatic amines, using methanol as the methylating agent, which is a sustainable chemical feedstock. Kinetic control of the aliphatic amine monomethylation was achieved by using a readily available ruthenium catalyst at an adequate temperature under hydrogen pressure. Various substrates including bio-related molecules and pharmaceuticals were selectively monomethylated, demonstrating the general utility of the developed method.

Photocatalyzed cascade Meerwein addition/cyclization of: N -benzylacrylamides toward azaspirocycles

A visible-light-induced cascade Meerwein addition/cyclization of alkenes involving C-F bond cleavage was developed. This method offers a rapid access to azaspirocyclic cyclohexadienones from N-benzylacrylamides via C-F bond cleavage applying H2O as an external oxygen source, allowing for the incorporation of various aromatic moieties originating from aryldiazonium salts.

Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome

On the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency or poor metabolic stability. We conducted a phenotypic screen and identified a micromolar hit with novel amide structure. Medicinal chemistry efforts yielded a highly potent, selective, and metabolically stable drug candidate, compound 56 (RIPA-56). Biochemical studies and molecular docking revealed that RIP1 is the direct target of this new series of type III kinase inhibitors. In the SIRS mice disease model, 56 efficiently reduced tumor necrosis factor alpha (TNFα)-induced mortality and multiorgan damage. Compared to known RIP1 inhibitors, 56 is potent in both human and murine cells, is much more stable in vivo, and is efficacious in animal model studies.

NECROSIS INHIBITORS

The invention provides amides that inhibit cellular necrosis and/or human receptor interacting protein 1 kinase (RIP1), including corresponding sulfonamides, and pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition.

Oxidation potentials of N-modified derivatives of the analgesic flupirtine linked to potassium KV7 channel opening activity but not hepatocyte toxicity

Openers of neuronal voltage-gated potassium channels (KV) are of interest as therapeutic agents for treating pain (flupirtine) and epilepsy (retigabine). In an effort to better understand the mechanisms of action and toxicity of flupirtine, we synthesized nine novel analogues with varying redox behavior. Flupirtine can be oxidatively metabolized into azaquinone di-imines; thus, the oxidation potentials of flupirtine and its analogues were measured by cyclic voltammetry. KV7.2/3 (KCNQ2/3) opening activity was determined by an established assay with HEK293 cells overexpressing these channels. A link was found between the oxidation potentials of the compounds and their EC50 values for potassium channel opening activity. On the other hand, no correlation was observed between oxidation potentials and cytotoxicity in cultures of transgenic mouse hepatocytes (TAMH). These results support the idea that oxidative metabolites of flupirtine contribute to the mechanism of action, similar to what was recently proposed for acetaminophen (paracetamol), but not to hepatotoxicity.

Selective N-methylation of aliphatic amines with CO2 and hydrosilanes using nickel-phosphine catalysts

A method using CO2 and PhSiH3 for the methylation of primary and secondary aliphatic amines catalyzed by Ni (0) complexes was developed, selectively producing the monomethylated products in moderate to good yields. For that purpose, two catalysts were used: [(dippe)Ni(μ-H)]2 and the commercially available Ni(COD)2/dcype, both of which were rather efficient in this process. With a slight experimental modification, the reaction allowed the production of monomethylated ureas in good yields by using low amounts of PhSiH3. On the basis of the experimental results, we propose a possible reaction mechanism for the formation of the new C-N bond.

Selective monomethylation of primary amines with simple electrophiles

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.

Highly enantioselective synthesis of tetrahydroquinolines via cobalt(II)-catalyzed tandem 1,5-hydride transfer/cyclization

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.

Discovery of microsomal triglyceride transfer protein (MTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide

Analogues related to dirlotapide (1), a gut-selective inhibitor of microsomal triglyceride transfer protein (MTP) were prepared with the goal of further reducing the potential for unwanted liver MTP inhibition and associated side-effects. Compounds were designed to decrease active metabolite load: reducing MTP activity of likely human metabolites and increasing metabolite clearance to reduce exposure. Introduction of 4′-alkyl and 4′-alkoxy substituents afforded compounds exhibiting improved therapeutic index in rats with respect to liver triglyceride accumulation and enzyme elevation. Likely human metabolites of select compounds were prepared and characterized for their potential to inhibit MTP in vivo. Based on preclinical efficacy and safety data and its potential for producing short-lived, weakly active metabolites, compound 13 (PF-02575799) advanced into phase 1 clinical studies.