Synthesis of β‐phenylethylamine derivatives X<i>N</i>‐(hydroxy‐ and methoxy‐aralkyl) derivatives

Dijk, J. van; Moed, H. D.

doi:10.1002/recl.19730921113

Cited by 7 publications

(1 citation statement)

References 10 publications

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“…[26] Hence, the bromo analogue 16 d (R 1 = Br, R 2 = THP) was prepared as the tetrahydropyranoyl ether from 12 by protection of the hydroxy group with 3,4-dihydro-2H-pyran to give 15 and subsequent reduction of the ester group as described by Mori and Takechi. [33] The 2-phenylethanol derivatives 16 a-d were converted into the alkyl bromides 17 a-d by using PBr 3 (for 17 a) [34] or Ph 3 PBr 2 (for 17 b and 17 c) or CBr 4 /Ph 3 P (for 17 d), which were then used to alkylate the anion of 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile (7) to give the triazolyl derivatives 18 a-d in moderate yields. [26,29] The deprotection of 18 a-d by catalytic hydrogenation (for 18 a-c, R 2 = Bn) or acid-catalysed solvolysis in MeOH (for 18 d, R 2 = THP) gave the phenols 19 a-d, which were sulfamoylated according to the conditions described by Okada et al [35] with excess sulfamoyl chloride in N,N-dimethylacetamide (DMA) to give the sulfamates 20 a-d in good yields.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4‐(4H‐1,2,4‐triazol‐4‐ylamino)benzonitrile: SAR, Crystal Structures, in vitro and in vivo Activities

et al. 2008

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4-(((4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6 a) was the first dual aromatase-sulfatase inhibitor (DASI) reported. Several series of its derivatives with various linker systems between the steroid sulfatase (STS) and the aromatase inhibitory pharmacophores were synthesised and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors 42 d and 60, and DASI 43 h were determined. Nearly all derivatives show improved in vitro aromatase inhibition over 6 a but decreased STS inhibition. The best aromatase inhibitor is 42 e (IC(50)=0.26 nM) and the best DASI is 43 e (IC(50 aromatase)=0.45 nM, IC(50 STS)=1200 nM). SAR for aromatase inhibition shows that compounds containing an alkylene- and thioether-based linker system are more potent than those that are ether-, sulfone-, or sulfonamide-based, and that the length of the linker has a limited effect on aromatase inhibition beyond two methylene units. Compounds 43 d-f were studied in vivo (10 mg kg(-1), single, p.o.). The most potent DASI is 43 e, which inhibited PMSG-induced plasma estradiol levels by 92 % and liver STS activity by 98 % 3 h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers.

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Section: Chemistrymentioning

confidence: 99%

Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4‐(4H‐1,2,4‐triazol‐4‐ylamino)benzonitrile: SAR, Crystal Structures, in vitro and in vivo Activities

et al. 2008

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Umpolung der Reaktivität von Aminen. Nucleophile α‐sek.‐Aminoalkylierung über metallierte Nitrosamine

Seebàch¹,

Enders²

1975

Angewandte Chemie

124

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Es gibt prinzipiell zwei Arten von Heteroatomen in organischen Molekiilen: Die einen machen das mit ihnen verbundene Kohlenstoffatom zu einem elektrophilen, die anderen zu einem nucleophilen Zentrum. Die Entwicklung von Methoden zum Uberwechseln zwischen den beiden darauf beruhenden Kategorien von Reagentien ist eine wichtige Aufgabe der modernen organischen Synthese. Moglichkeiten dieser Umpolung der Reaktivitat funktioneller Gruppen werden am Beispiel der Amine diskutiert. Eine Methode zur Herstellung von maskierten a-sek.-Aminocarbanionen besteht darin, daD man das sekundare Amin nitrosiert, das entstandene Nitrosamin in a-Stellung zum Stickstoff metalliert, mit Elektrophilen umsetzt und entnitrosiert. Fur jeden dieser Schritte wird eine Anzahl von Beispielen gegeben, die die groBe Anwendungsbreite der synthetischen Gesamtoperation (elektrophile Substitution am a-C-Atom des sekundaren Amins) belegen. Erste Anwendungen und ein Verfahren zur Umgehung des Hantierens von Nitrosaminen werden vorgestellt, und zum SchluD wird die Bedeutung der Nitrosamine fur die Carcinogenese-und Mutageneseforschung kurz erortert.

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Umpolung of Amine Reactivity. Nucleophilic α‐(Secondary Amino)‐alkylation via Metalated Nitrosamines

Seebàch¹,

Enders²

1975

Angew. Chem. Int. Ed. Engl.

205

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There are basically two kinds of hetero atoms in organic molecules: one kind confers electrophilic character upon the carbon atom to which it is bound, and the other kind turns it into a nucleophilic site. The development of methods permitting transitions between the two resulting categories of reagents has become an important task of modern organic synthesis. The scope of such umpolung of the reactivity of functional groups is discussed for the case of amines as an example. A method of preparing masked u-secondary amino carbanions consists in nitrosation of the secondary amine, followed by metalation of the resulting nitrosamine CL to the nitrogen, reaction with electrophiles, and subsequent denitrosation. Many examples are given for each of these steps which illustrate the wide scope of the overall synthetic operation (electrophilic substitution at the a-C atom of the secondary amine). Preliminary applications and a method for avoiding the handling of nitrosamines are presented, and the report concludes with a brief account of the significance of nitrosamines in the study of carcinogenesis and mutagenesis. Table 2. Examples for umpolung of carbonyl compounds and amines. Newly formed bonds are shown in bold print. Attack Reagent Equivalent Product type Ref.

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Synthesis of β‐phenylethylamine derivatives XN‐(hydroxy‐ and methoxy‐aralkyl) derivatives

Cited by 7 publications

References 10 publications

Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4‐(4H‐1,2,4‐triazol‐4‐ylamino)benzonitrile: SAR, Crystal Structures, in vitro and in vivo Activities

Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4‐(4H‐1,2,4‐triazol‐4‐ylamino)benzonitrile: SAR, Crystal Structures, in vitro and in vivo Activities

Umpolung der Reaktivität von Aminen. Nucleophile α‐sek.‐Aminoalkylierung über metallierte Nitrosamine

Umpolung of Amine Reactivity. Nucleophilic α‐(Secondary Amino)‐alkylation via Metalated Nitrosamines

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