38925-76-7

Upstream product

• 64-04-0 phenethylamine 
• 156747-42-1 3-<4-(Trifluoromethyl)benzoyl>-2-oxazolidinone 
• 329-15-7 4-trifluoromethyl-phenyl acetyl chloride 
• 6926-44-9 phenethyl azide 
• 455-24-3 4-trifluoromethylbenzoic acid 
• 455-19-6 4-Trifluoromethylbenzaldehyde 

Downstream Products

• 1159997-91-7 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline 
• 1159996-43-6 (R)-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide 
• 757880-98-1 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline 
• 1159996-20-9 N-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide 
• 1159996-53-8 (R)-1-(1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone 
• 1159997-92-8 (R)-(-)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline 
• 1240692-10-7 5-phenyl-2-(4-(trifluoromethyl)phenyl)oxazole 
• 1589601-97-7 1-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline 
• 1589601-96-6 2-benzyl-1-methyl-1-(4-(trifluoromethyl)-phenyl)-1,2,3,4-tetrahydroisoquinoline 
• 1589602-12-9 C₂₃H₁₉F₃N⁽¹⁺⁾*Br^(1-) 
• 1589602-06-1 N-(4-fluorophenyl)-1-methyl-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide 
• 1589602-05-0 (R)-N-(2,2,2-trifluoro-1-phenylethyl)-1-(4-(trifluoromethyl)-phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide 
• 1159997-65-5 (R)-1-(4-(trifluoromethyl)phenyl)-N-((R)-1,1,1-trifluoropropan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide 
• 1159997-27-9 (R)-1-(4-(trifluoromethyl)phenyl)-N-((S)-1,1,1-trifluoropropan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide 

Relevant academic research and scientific papers

Asymmetric Transfer Hydrogenation of Unhindered and Non-Electron-Rich 1-Aryl Dihydroisoquinolines with High Enantioselectivity

The use of arene/Ru/TsDPEN catalysts bearing a heterocyclic group on the TsDPEN in the asymmetric transfer hydrogenation (ATH) of dihydroisoquinolines (DHIQs) containing meta- or para-substituted aromatic groups at the 1-position results in the formation of products of high enantiomeric excess. Previously, only 1-(ortho-substituted)aryl DHIQs, or with an electron-rich fused ring gave products with high enantioselectivity; therefore, this approach solves a long-standing challenge for imine ATH.

Josiphos-Type Binaphane Ligands for Iridium-Catalyzed Enantioselective Hydrogenation of 1-Aryl-Substituted Dihydroisoquinolines

Convenient synthesis and useful application of a series of Josiphos-type binaphane ligands were described. The iridium complexes of these chiral diphosphines displayed excellent enantioselectivity and good reactivity in the asymmetric hydrogenation of challenging 1-aryl-substituted dihydroisoquinoline substrates (full conversions, up to >99% ee, 4000 TON). The use of 40% HBr (aqueous solution) as an additive dramatically improved the asymmetric induction of these catalysts. This transformation provided a highly efficient and enantioselective access to chiral 1-aryl-substituted tetrahydroisoquinolines, which were of great importance and common in natural products and biologically active molecules.

Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective Inhibitors

Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biological evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 "open" conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based 3g and 3n exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, respectively. Selectivity over other class I isoforms was comparable or better, whereas inhibition of HDAC6, a class II HDAC isoform, was below 50% at 10 μM. The cytotoxicity of 3g and 3n was evaluated in neuroblastoma cell lines, and 3n displayed concentration-dependent cytotoxicity similar to or better than that of PCI-34051. The selectivity of 3g and 3n was confirmed in SH-SY5Y cells as both did not increase the acetylation of histone H3 and α-tubulin. Discovery of the novel TIQ chemotype paves the way for the development of HDAC8 selective inhibitors for therapeutic applications.

Direct oxidative amidation of aldehydes with amines catalyzed by heteropolyanion-based ionic liquids under solvent-free conditions via a dual-catalysis process

A simple and efficient procedure for the synthesis of amides directly from aldehydes and amines catalyzed by heteropolyanion-based ionic liquids under solvent-free conditions has been reported. The practical protocol was found to tolerate a wide range of substrates with different functional groups. Moderate to excellent yields, solvent-free media, and operational simplicity are the main highlights. The proposed dual-catalysis mechanistic pathway was briefly investigated. Furthermore, the heteropolyanion-based ionic liquids were easily reusable for this oxidative amidation.

Optimization of potency and pharmacokinetic properties of tetrahydroisoquinoline transient receptor potential melastatin 8 (TRPM8) antagonists

Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 °C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values 3 mg/kg.

Zinc(II)-catalyzed oxidative amidation of arylaldehydes with alkylamines under solvent-free conditions

The first zinc-catalyzed oxidative amidation of arylaldehydes has been developed. Various amides were prepared in good yields under solvent-free and mild reaction conditions.

Phosphine-based redox catalysis in the direct traceless staudinger ligation of carboxylic acids and azides

Redox catalysis: Aryl amides, imides, lactams, and dipeptides are obtained through a direct Staudinger ligation mediated by phosphine-based redox catalysis (see scheme). Mechanistic studies indicate the involvement of a phosphonium carboxylate intermediate that leads to a 1,3-acyl migration and thus results in C-N bond formation. Copyright

Fused piperidines as a novel class of potent and orally available transient receptor potential melastatin type 8 (TRPM8) antagonists

The transient receptor potential melastatin type 8 (TRPM8) is a nonselective cation channel primarily expressed in a subpopulation of sensory neurons that can be activated by a wide range of stimuli, including menthol, icilin, and cold temperatures (25 °C). Antagonism of TRPM8 is currently under investigation as a new approach for the treatment of pain. As a result of our screening efforts, we identified tetrahydrothienopyridine 4 as an inhibitor of icilin-induced calcium influx in CHO cells expressing recombinant rat TRPM8. Exploration of the structure-activity relationships of 4 led to the identification of a potent and orally bioavailable TRPM8 antagonist, tetrahydroisoquinoline 87. Compound 87 demonstrated target coverage in vivo after oral administration in a rat pharmacodynamic model measuring the prevention of icilin-induced wet-dog shakes (WDS).

A highly efficient and enantioselective access to tetrahydroisoquinoline alkaloids: Asymmetric hydrogenation with an iridium catalyst

Efficient and enantioselective: Using the iodine-bridged dimeric iridium complex [{Ir(H)[(S,S)-(f)-binaphane]}2(μ-I)3] +I- (1) a wide range of tetrahydroisoquinoline alkaloids, including the substructure of the pharmaceutical drug solifenacin, were obtained with excellent enantioselectivities and high turnover numbers (see scheme). Copyright

Formal nucleophilic substitution of bromocyclopropanes with amides en route to conformationally constrained β-amino acid derivatives

A chemo- and diastereoselective protocol for the formal nucleophilic substitution of 2-bromocyclopropylcarboxamides with secondary amides is described. This method allows for convergent and highly selective synthesis of trans-β-aminocyclopropane carboxylic acid derivatives.