Phenylethylamine analogs

U.S. Drug Enforcement Administration Fentanyl Analogs Phenylethylamine Analogs Methamphetamine MDMA... 

The deamination of primary amines such as phenylethylamine by Escherichia coli (Cooper et al. 1992) and Klebsiella oxytoca (Flacisalihoglu et al. 1997) is carried out by an oxidase. This contains copper and topaquinone (TPQ), which is produced from tyrosine by dioxygenation. TPQ is reduced to an aminoquinol that in the form of a Cu(l) radical reacts with O2 to form H2O2, Cu(ll), and the imine. The mechanism has been elucidated (Wihnot et al. 1999), and involves formation of a Schiff base followed by hydrolysis in reactions that are formally analogous to those involved in pyridoxal-mediated transamination. 

Chemical Structures. Figure 1 shows the chemical structures for 14 phenylethylamine compounds. Nine of these compounds are used clinically as anorectics (ii-amphetamine, phentermine, diethylpropion, phenmetrazine, phendimetrazine, clotermine, chlorphentermine, benzphetamine, and fenfluramine). Four of these compounds are not approved for clinical use and are reported to have hallucinogenic properties (MDA, PMA, DOM, and DOET). The final compound ( /-ephedrine) is used clinically for bronchial muscle relaxation, cardiovascular, and mydriatic effects. Figure 2 shows the chemical structure for MDMA, the methyl analog of MDA. MDMA is not approved for clinical use and has been reported to produce both LSD-like and cocaine-like effects. 

Epipolasin-B (61), mp 92 °C, was one of two isothiocyanates obtained from the sponge Epipolasis kushimotogensis. Neither the isonitrile nor formamido analog were found with the isothiocyanate. Instead, the thiourea adduct of /J-phenylethylamine was isolated along with another isothiocyanate-thiourea pair [51]. The absolute configuration of 61 was determined by appropriate... 

The CSAs that have been used most widely are 2,2,2-trifluoro-l-phenylethanol (TFPE, la), 2,2,2-trifluoro-l-(l-naphthyl)ethanol (TFNE, lb), 2,2,2-trifluoro-l-(9-anthryl)ethanol (TFAE, Ic), 1-phenylethylamine (PEA, 2a), and l-(l-naphthyl)ethylamine (NEA, 2b). Both enantiomers of TFPE, TFAE (9), PEA, and NEA are commercially available. The fluoroalcohols are relatively acidic and interact strongly with solutes having one or more basic sites (Sect. IV-B). Amines 2 have been used most often as CSAs for organic acids or other acidic solutes (Sect. IV-C). A number of analogs of TFAE have been studied (Sect. III-C). 

Tyramine is derived by using 4-hydroxybenzaldehyde as the starting material. Vanillin and 0-vanillin can also be used in this synthesis to make the tyramine analogs 2-hydroxy-3-methoxy-B-phenylethylamine and 3-methoxy-4-hydroxy-B-phenylethylamine, respectively. Vanillin is less suspicious to purchase and the potency and elfects of the vanillin made drug are about the same as Tyramine. 

On comparing the activities of the five compounds for which numerical estimates are available in all three assays (synephrine, octopamine, phenylethanolamine, norepinephrine and tyramine) the rank orders of potency in the three systems are Crayfish, 1,2,3t4,5 Cockroach, 2,1,3,4,5 Locust 1,2,3t5,4. This indicates a basic similarity in the responses of these preparations. In each case it was found that ring hydroxylation of the phenylethylamine nucleus was not essential for activity, although p-hydroxylation does yield the best activity. This is particularly evident in the crayfish study where a-MAMBA (a-methylaminomethyl benzyl alcohol), the analog of synephrine which lacks ring substitution, was one of the most active compounds tested, and 3-phenylethanolamine, the corresponding analog of OA, is almost as active as OA. The base compound for this series, phenylethylamine, also shows appreciable activity, but only in the crayfish assay. 

Polavarapu et al. (60) have obtained FTIR-VCD (1625-600 cm ) for neat samples of the three substituted a-phenylethanes, 10, X = NH2, OH, NCO. In (-F)-a-phenylethylamine, seven VCD bands are observed, all with positive sign. Features near 1370 and 1200 cm were identified as possibly useful probes for the configuration of similar analogs. 

Bicyclic ester 100 forms in analogy to isomeric ester 65 (Section 2.4.1.1) (07JOC5608). /l-Phenylethylamine 101 undergoes palladium-catalyzed direct aromatic carbonylation, thus providing another synthesis of benzo-lactam 78b (06JOC5951). A stereoselective nitro-Mannich/lactamization cascade of y-nitro ester and cyclic imine affords polysubstituted lactam 102 (08OL4267). 

The reaction of racemic A-phthalimido-S-p-tolyl-S-vinylsulfoximine with a deficiency (0.5 molar equiv) of enantiomerically pure (-)-ephedrine resulted in a kinetic resolution of the vinyl sulfoximine.113 When the reaction was conducted at -30 °C the unreacted vinyl sulfoximine could be recovered with an enantiomeric purity of 46%. (-)-Amphetamine and (+)-l-phenylethylamine were not effective for kinetic resolution. The analogous (Z)-propenyl sulfoximine also underwent kinetic resolution with (-)-ephedrine, but the extent of kinetic resolution was not determined. 

An enantioselective synthesis of TIQ-1-carboxylic acids 91a,b has recently been reported (279). Hydrolysis of the optically active methyl ether enantiomer of hydantoin 103 was accomplished by 20% sodium hydroxide in refluxing methyl cellosolve and led to the dimethyl ether analog of 91a, which was used to establish the absolute configuration of the products. Amino acids 91a,b have also been prepared by chemical resolution of the N,0-benzylated acid 108 with optically active 1-phenylethylamines. Catalytic debenzylation of enantiomer 109a gave... 

The method so far has been applied only to the resolution of dZ-menthol. Its range doubtless can be extended still further by repladng Z-rhenthylamine with other readily available terpenoid amines such as the active carvomenthyl-, thujyl-, and fenchyl-amines as ell as simpler amines like a-phenylethylamine and its analogs. - ... 

Evaluation of Some Bicyclic Systems as Conformationally-Defined Phenylethylamines. X-Ray Crystallography. Perhaps the ultimate test of the suitability of a chemical structure for preparing conformationally-defined analogs would be their ability to produce biological effects identical to those of the parent compound. Since this ideal is rarely achieved, and since a "wrong" conformer should be inactive, it is useful to have other criteria with which to evaluate these systems. The bicyclic molecules to be examined in the present study are compounds I-VIII (Figure 7), benzobicyclo[2.2.2]octenes, benzobicyclo [2.2.1]heptenes, and 1,2,3,4-tetrahydro-l,4-epoxynaphthalenes. A number of structural parameters... 

Figure 7. Conformationally defined analogs of phenylethylamines (see text)...

Figure 8. Observed values of n from x-ray crystallography of phenylethylamines showing the agreement with the value of this angle from molecular orbital studies and some conformationally defined analogs (see text)...

Figure 12. Comparison of the distances from the nitrogen to the para-oxygen in some conformationally defined analogs of phenylethylamines with those found from x-ray crystallographic studies reported for phenylethylamines (see text)...

As a close analog to 1-phenylethylamine but possessing greater steric hindrance, (5)-l-naph-thylethylamine has been employed as an auxiliary for the alkylation of azaenolates via imines (Section D. 1.1.1.4.) and amides (Section D.1.5.1.). The racemate (obtained by reductive amina-tion of 1-acetylnaphthalene) is best resolved w ith tartaric acid16 (see also ref 17). 

Q-l-Phenylethylamine is the chiral starting material for the preparation of the CHIRAMT ligands11 which were similarly used (Sections D.l.5.2.1. and D.1.5.8.). Analogously, H R-NEAT was prepared from (7 )-l-(l-naphthyl)ethylamine12. 

The early literature describes examples of elimination reactions of a rather forcing nature which have not been explored further. For example, the elimination of HCl from (2-chloroethyl)phosphonic dichloride occurs over BaCl2 at 330 and dechlorination of (l,2-dichloroethyl)phosphonic diesters occurs on heating with zinc dust. Dehydrochlorination of a (2-chloroalkyl)phosphonic acid occurs on simple pyrolysis but the preferred procedure consists in the treatment of the acid diester with Et3N in warm benzene, a procedure also used for analogous (2-chloroethyl)phosphinic esters ". The dehydro-halogenation of isopropyl (2-haloethyl)phenylphosphinate by a chiral tertiary amine, such as quinine, quinidine, 1 -phenylethylamine or A-methylephedrine, in a less than equivalent quantity, affords an enrichment of one enantiomer of the ethenylphenylphosphinic... 

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