Amines Phenethylamines

In 1911, Ame Pictet and Theodor Spengler reported that P-arylethyl amines condensed with aldehydes in the presence of acid to give tetrahydroisoquinolines. Phenethylamine 6 was combined with dimethoxymethane 7 and HCl at elevated temperatures to give tetrahydroisoquinoline 8. Soon after, the Pictet-Spengler reaction became the standard method for the formation of tetrahydroisoquinolines. 

The A-substituted derivatives of 4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxamides and -3-acetamides and l,6-dimethyl-4-oxo-1,6,7,8-tetrahy-dro-4//-pyrido[l,2-n]pyrimidine-3-carboxamide were prepared by treatment of the appropriate 3-carboxylic acids and acetic acid, first with an alkyl chloroformate in the presence ofNEt3 in CHCI3 below — 10°C, then with an amine (98ACH515). A-Phenethyl and A-[2-(3,4-dimethoxyphenyl)ethyl] derivatives of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetamide were obtained in the reaction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-3-acetic acid and phenethylamines in boiling xylene under a H2O separator. Hydrazides of 4-oxo-4//- and 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic acid were prepared from the appropriate ester with H2NNH2 H2O in EtOH. Heating 4-oxo-4//- and 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic hydrazides in EtOH in the presence of excess Raney Ni afforded fhe appropriafe 4-oxo-6,7,8,9-fefrahydro-4//-pyrido[l,2-n]pyrimidine-3-acefa-mide. In the case of the 4-oxo-4// derivative, in addition to N-N bond... 

Addition of Grignard and organolithium reagents to imines 2. derived from enantiomerically pure (S)-valinol (1), provides a-substituted phenethylamines 3 in moderate to good yield and excellent diastereoselectivity (in each case only one diastereomer can be detected by NMR)15. By appropriate selection of imine and organometallic reagent both diastereomeric amines are accessible (see also refs 16 and 17). 

Evaluation of the above route against our initial target objectives for the synthesis of taranabant indicated a high level of success, not just for the primary objectives of removing the tin chemistry and chiral chromatography, but for a number of other process improvements (Table 9.2). Of particular note was that the three crystalline intermediates were key for purification, first the phenethylamine salt 12 for the classical resolution, secondly the HC1 salt of amine 2 allowed for upgrade of diastereomeric purity, and finally the API allowed for upgrade of enantiomeric purity via initial removal of racemic material. 

A rather complex fused isoindoline (87) has been found to show good anorectic activity. This substance differs from other anorectic agents by not being a p-phenethylamine analogue. Preparation of this compound starts by reaction of a substituted benzoyl-benzoic acid (82) with ethylene diamine. The product (84) can be rationalized as being the aminal from the initially obtained monoamide 83. This is then subjected to reduction with lithium aluminum hydride... 

The intramolecular photoelimination of HC1 from JV-chloroacetyl derivatives of suitable amines is a useful and versatile approach to the synthesis of azaheterocycles. The iV-chloroacetyl derivative 357 has been converted in this way to 7-oxodesethylcatharanthine (358) in 55% yield.300 Investigations in this area have been particularly concerned with the A-chloroacetyl derivatives of benzylamines and phenethylamines the N-chloroacetyl-benzylamine 359 on irradiation affords the two 3-oxo-l,2,3,4-tetrahydroiso-quinolines 360 and 361.301 Competing photocyclizations have been observed in the case of l-[3-(chloroacetylamino)propyl]-3-methylindole (362) which is converted into three photoproducts, 363, 364, and 365.302... 

A Ar-B is( benzotri azoly I methy Famines 638 derived from benzyl or phenethylamines undergo cyclocondensation with allylsilanes catalyzed by S11CI4 to give 4-chloropiperidines 640 (Scheme 99) <1999JOC3328>. This [3+3] cyclocondensation is assumed to proceed in two steps via intermediate 639. [3+4] cyclocondensation of derivatives 638, originating from various aromatic and aliphatic amines, with dilithiated benzamides leads to 2,4-benzodiazepin-1-ones 641 <2002JOC8237>. 

Taken together, the data presented here show that many phenyl- and in-dolealkylamines are hallucinogenic in man and behaviorally active in animals. In both series, primary amines penetrate the blood-brain barrier with difficulty, although this seems to be more of a problem with tryptamines (and even N-monoalkyltryptamines) than with phenethylamines. This situation is somewhat alleviated in the presence of an alpha-methyl substituent. The primary amines are also prone to rapid metabolism by oxidative deamination. Metabolism, however, can be impeded by the presence of an alpha-methyl or N-alkyl function. 

Either phenethylamine or phenylisopropylamine will work. If the hydrochloride salt is available, this should first be changed to the free amine by stirring with concentrated aqueous NaOH. 

O. 016 mole of the amine and then 3.6 g of formaldehyde (ca. 10 ml of formalin) and reflux for 5 hours. Cool to room temperature, add 7 ml concentrated HCI and evaporate in vacuum. The resulting oily dimethylamine can be purified by dissolving in 25 ml water, extracting with 2X25 ml CHCI3. Basify the aqueous layer with 2N NaOH and extract with 3X25 ml ether, and proceed as described above for the N-methylamines. This procedure should work for both phenethylamines and phenylisopropylamines, and should affect the trip similarly to N-monomethylation. 

Tyramine (4-hydroxy-phenethylamine, para-tyramine, / -tyramine) A phenolic amine CgHnNO, a monoamine compound derived from the amino acid tyrosine. 

A sensitive method for primary amines is shown in reaction 2, leading to the corresponding 7V-benzenesulfonyl-/V-trifluoroacetyl derivatives. These can be determined by GC-ECD using SE-30 columns LOD 1-5 pg, which is about 200 times more sensitive than GC-FID. The method was applied for determination of phenethylamine (33) in urine110. This analysis was performed also by LLE into n-pentane, derivatization to the benzenesulfonamide and GC-FPD using a capillary column recoveries of aliphatic primary amines in urine were 91-107%, RSD 0.2-4.5%111,112. Amines in environmental waters and sediments were determined after LLE with dichloromethane, derivatization with benzenesulfonyl chloride and GC-SIM-MS LOD 0.02-2 pg/L of water and 0.5-50 ng/g of sediment113. 

Amino acids may be determined by measuring the amines obtained after the action of a carboxylase with a specific electrode for amines, which is based on a poly(vinyl chloride) membrane containing sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (166) as ion exchanger and tricresyl phosphate as solvent mediator. LOD was 20 and 50 i-M for tyroxine and phenylalanine, determined as tyramine (5) and phenethylamine (33), respectively364. 

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