A Practical Synthesis of 2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-(piperidin-4-yl)-1H-imidazol-1-yl}-N,N-dimethylethanamine

Vaid, Radhe K.; Spitler, Jeremy T.; Boini, Sathish K.; Henry, Kenneth J.; Xu, Jian‐Xin; Gao, Baitao; Lu, Xiaoquan

doi:10.1055/s-0031-1290371

Cited by 3 publications

(3 citation statements)

References 8 publications

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“…The N -protected β-alanine 2 was readily prepared by refluxing the mixture of isobenzofuran-1,3-dione 1, β-alanine and acetic acid for 4 hours according to literature 38 39 with appropriate revision. Then intermediate 2 was condensed with 2-(4-methoxyphenyl)ethanamine hydrochloride at room temperature to give intermediate 3 in high yield 40 .…”

Section: Chemistrymentioning

confidence: 99%

Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

Yang

Ang

Long

et al. 2016

Sci Rep

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A scaffold-hopping strategy toward Agomelatine based on in silico screening and knowledge analysis was employed to design novel antidepressant agents. A series of 3, 4-dihydroisoquinoline compounds were selected for chemical synthesis and biological assessment. Three compounds (6a-1, 6a-2, 6a-9) demonstrated protective effects on corticosterone-induced lesion of PC12 cells. Compound 6a-1 also displayed low inhibitory effects on the growth of HEK293 and L02 normal cells and it was further evaluated for its potential antidepressant effects in vivo. The forced swim test (FST) results revealed that compound 6a-1 remarkably reduced the immobility time of rats and the open field test (OFT) results indicated a better general locomotor activity of the rats treated with compound 6a-1 than those with Agomelatine or Fluoxetine. Mechanism studies implied that compound 6a-1 can significantly reduce PC12 cell apoptosis by up-regulation of GSH and down-regulation of ROS in corticosterone-induced lesion of PC12 cells. Meanwhile, the down-regulation of calcium ion concentration and up-regulation of BDNF level in PC12 cells may account for the neuroprotective effects. Furthermore, compound 6a-1 can increase cell survival and cell proliferation, promote cell maturation in the rat hippocampus after chronic treatment. The acute toxicity data in vivo indicated compound 6a-1 exhibited less hepatotoxicity than Agomelatine.

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Section: Chemistrymentioning

confidence: 99%

Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

Yang

Ang

Long

et al. 2016

Sci Rep

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show abstract

“…On the basis of a report in the literature, 17 we attempted an alternative synthesis of diamine 19 by reductive amination on a palladium/carbon catalyst of the imine generated in situ by condensing keto aldehyde 24 with N,N-dimeth- (12) in methanol, but this was unsuccessful. Similarly, attempts to synthesize diamine 19 by direct alkylation of amino ketone 3 with chloro amine 7 failed.…”

Section: Scheme 4 Attempted Syntheses Of the Protected Intermediate 2mentioning

confidence: 99%

“…Because of our interest in kinase inhibitors, 11 we were interested in developing an efficient synthesis of (2-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethylamine (9), and we recently reported a synthesis of the title compound through hydrogenation of its pyridinyl analogue 8 (Scheme 1). 12 Although, this is a practical synthesis, it involves the use of the lachrymator 1, which requires special handling in large-scale production. Also, the synthesis of amine 3 from intermediate 2 produces formaldehyde, the handling of which required special controls with respect to personnel exposure and disposal.…”

mentioning

confidence: 99%

Synthesis of (2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethylamine

et al. 2013

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An efficient eight-step synthesis of the title compound, starting from oxoacetic acid monohydrate, was developed. Condensation of oxoacetic acid monohydrate with N,N-dimethylethanamine followed by reductive amination and protection gave N-(tertbutoxycarbonyl)-N-[2-(dimethylamino)ethyl]glycine. Activation of this intermediate with 1,1′-carbonylbis-1H-imidazole followed by treatment with (methoxyamino)methane gave tert-butyl [2-(dimethylamino)ethyl]{2-[methoxy(methyl)amino]-2-oxoethyl}carbamate, which upon reaction with [4-fluoro-3-(trifluoromethyl)phenyl]magnesium bromide, generated in situ, and subsequent deprotection gave 2-{[2-(dimethylamino)ethyl]amino}-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone dihydrochloride. Coupling of this diamine with an activated carboxylic acid gave tert-butyl 4-{1-[2-(dimethylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidine-1-carboxylate, which on treatment with sodium acetate in ethanol followed by deprotection in situ and neutralization gave the title compound in good yield.

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Propylphosphonic anhydride (T3P®): An expedient reagent for organic synthesis

Waghmare¹,

Hindupur²,

Pati³

2014

Ref. J. Chem.

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A Practical Synthesis of 2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-(piperidin-4-yl)-1H-imidazol-1-yl}-N,N-dimethylethanamine

Cited by 3 publications

References 8 publications

Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

Synthesis of (2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethylamine

Propylphosphonic anhydride (T3P®): An expedient reagent for organic synthesis

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