Amines phenylacetic acid derivative

In practically all theories of the biosynthesis of quinazolines, anthranilic acid or an equivalent is regarded as one of the building blocks. Robinson 158) postulated that anthranilic acid (N-methylated where necessary), ammonia or amine, and formic acid or phenylacetic acid derived from phenylalanine units or their equivalents build up the simple substituted quinazoline derivatives. Thus vasicine (28) may be derived from anthranilic acid and proline, or closely related metabolites. Febrifugine (9) possibly could be formed from anthranilic acid, formic acid, ammonia, a Cj-unit, and lysine or equivalent compounds. For... 

The synthesis and metabolism of trace amines and monoamine neurotransmitters largely overlap [1]. The trace amines PEA, TYR and TRP are synthesized in neurons by decarboxylation of precursor amino acids through the enzyme aromatic amino acid decarboxylase (AADC). OCT is derived from TYR. by involvement of the enzyme dopamine (3-hydroxylase (Fig. 1 DBH). The catabolism of trace amines occurs in both glia and neurons and is predominantly mediated by monoamine oxidases (MAO-A and -B). While TYR., TRP and OCT show approximately equal affinities toward MAO-A and MAO-B, PEA serves as preferred substrate for MAO-B. The metabolites phenylacetic acid (PEA), hydroxyphenylacetic acid (TYR.), hydroxymandelic acid (OCT), and indole-3-acetic (TRP) are believed to be pharmacologically inactive. 

The coupling of the selone to racemic carboxylic acids with dicyclohexylcarbodiimide in dichloromethane with 4-dimethylaminopyridine at 0°C for 0.5-1 hour affords the acylated derivatives. Similar results are obtained using the acid chloride and triethyl amine. Figure 13 (upper part) shows the selenium spectrum for the diastereomeric. Y-acyl derivatives of the oxazo-lidine-2-selone with (A,A)-5-methylheptanoic acid. Clearly the shift difference of about (5 = 0.1 is sufficient for integration of the two singlets. The lower part of the figure shows the remarkably different 77Se resonances observed for four species derived from partially deuterated phenylacetic acid. The diastereomeric mixture of the monodeuteriated substance is easily detected (AS = 0.07, 5.0 Hz). 

In an indirect way the caprolactam salts may be formed by heating caprolactam solutions or suspensions of certain neutral or only slightly basic salts which are able to decompose to strong bases (82, 83, 86, 87, 91, 93). This effect can be reached by using alkali salts of carboxylic acids tending to decompose by decarboxylation. Alkali carbonates (7, 10, 13, 17, 28, 44, 45, 60, 65, 82—84, 87, 91, 102), alkali salts of carbonic monoalkyl esters, phenylacetic acid and other similar salts (62, 86, 89, 93, 102) are converted by decarboxylation into strongly basic carbonium salts or metal derivatives of amines or alcohols... 

Reactions at high dilution between the appropriate bis sulfenyl chlorides and primary amines have led in low yields to the 1,3,2-dithiazole derivatives (196) and (197), and nitrosation of substituted 2-mercapto-2-phenylacetic acids in Ac20 gives mesoionic compounds (12) (81LA1025). 

Sodium enolates of ketones and disodium enediolates of substituted phenylacetic acids reacted with activated aziridines to afford 7-amido ketones and 7-amidobutyric acids, respectively (Scheme 72). Aziridine-2-carboxylic acid esters can be utilized as versatile precursors for amino acid derivatives. Although the product distribution resulting from the reaction of activated aziridine-2-carboxylates with amines depends on the structure of the reactants, the reactions with alcohols or thiols in the presence of acidic cabilysts generally gave the a-amino acid derivatives (Scheme 73). ° On the other hand, free 3-methyl-2-aziridinecarboxylic acids (168) reacted with thiophenol, cysteine and glutathione to afford P-amino acid derivatives with sulfur substituents at the a-position as the main product (Scheme 73). ... 

The Curtius rearrangement of the acyl azide derived from optically pure a-methoxy-a-(trifluoro-methyl)phenylacetic acid (MTPA 48) also proceeds with retention of configuration, giving a-methoxy-a-(trifluoromethyl)benzyl isocyanate (49 equation 26). The isocyanate (49) is useful for the determination of the enantiomeric composition of optically active primary and secondary amines. 

A synthetic route to ( )-0,f>-dimethyltubocurarine iodide (CXXV), via the racemate of 0,0-dimethylbebeerine (CXXIII), was announced in 1959 by Tolkachev and his collaborators (94). It started by the condensation of 3-methoxy-4-hydroxyphenethylamine with 4-benzyloxy-phenylacetic acid to give the amide CXXVI. Reaction of the potassium salt of the latter with the methyl ester of 3-bromo-4-methoxyphenyl-acetic acid in the presence of copper powder gave compound CXXVII. This on condensation with 3-methoxy-4-hydroxy-5-bromophenethyl-amine afforded compound CXXVIII, which was methylated to CXXIX. The latter compound was cyclized with phosphorous oxychloride to the dihydroisoquinoline derivative CXXX. Debenzylation of CXXX followed by intramolecular Ullmann condensation yielded compound CXXXI. The latter was converted to racemic dimethylbebeerine (CXXIII) by reduction with zinc dust in acetic acid followed by methyla-tion. Finally, treatment of ( + )-CXXIII with methyl iodide furnished the dimethyl ether of ( + )-tubocurarine iodide, identified by comparison of its UV-spectrum with that of the dimethyl ether of natural tubo-curarine iodide and by melting-point determination of a mixture of the two specimens. 

In deacylation, as the enzyme cleaved the phenylacyl group, phenylacetic acid was formed, which lowered the pH of the reaction medium. Base was added to maintain the starting pH. (Note Use of ammonium hydroxide led to the formation of desilylated byproducts desilylation was eliminated when bicarbonates were used.) This approach was not required in the acylation reaction. At pH above 7.5 the (R)-and (S)-amines are practically insoluble in water. Organic solvents were used to extract the free amines from the aqueous reaction medium at pH 8.0. p-Fluoro-benzoyl, 1-naphthoyl, and phenylacetyl derivatives of the racemic amine were prepared and their behavior on the chiral HPLC column was studied. Based on ease of preparation and HPLC analysis, the 1-naphthoyl derivatives (Fig. 7) were preferred. Reversed phase HPLC analysis on a Vydac-C18 analytical column used a gradient of acetonitrile (0.1% triethylamine) in water (0.05% phosphoric acid) to quantify the total amide in the reaction mixture. Chiral HPLC analysis on (S,S) Whelk-O Chiral column used isopropanol hexane (30 70) as a solvent system to separate and quantify the (R)- and (S)-enantiomers. 

In all of the syntheses discussed, alkoxy derivatives of a-aminoaceto-phenone or of /3-phenethylamine were employed to supply the main structural outline of the isoquinoline system. Some of these amines are hard to obtain, especially if the resistant aromatic methoxyl groups are replaced by more sensitive substituents which may serve in the preparation of partly demethylated derivatives of papaverine or laudanosine. A significant innovation (60) which avoids the preparation of such unstable amines is the degradation of j3-phenylpropionic acid azides (hydrocinnamic acid azides) to the corresponding isocyanates, which add to the required phenylacetic acids probably with the intermediate formation of four-membered cyclic hemiacetals. The latter are transformed to A-carboxylic acids, which lose carbon dioxide and yield amides needed in the isoquinoline syntheses. In practice, the azide is heated with the phenylacetic acid in benzene solution for several hours, and the amide is isolated from the reaction mixture without difficulty. 

More recently (I )-0-acetylmandelic acid [(/ )-99], (S)-a -methoxy-a -(trifluoro-methyl)phenylacetic acid (MTPA) [(5 )-83] and other chiral acids have been used as CSAs. These acids form diastereomeric salts soluble in benzene- /6 or chloroform-d with a wide range of amines and amino alcohols, permitting a direct measure of their enantiomeric composition. EnantiomCTs of l,l -binaphth-2,2 -diol (100) and 1,1 -binaphth-2,2 -diylphosphoric acid (101) and other derivatives of 100 and 101 have also been successfully used as CSAs in chloroform- / and benzene- /6 for the estimation of enantiomeric excesses of a number of -amino alcohols , and enantiomers of 101 have been used for cyclic secondary and tertiary amines . ... 

N-Dealkylation (N-debenzylation) of tertiary amines with phosgene or phosgene equivalents has also been employed by a recently disclosed process for the preparation of o-(chloromethyl)phenylacetic add derivatives, which are important intermediates for the preparation of microbiddes. o-Chloromethylphenylacetic acid derivatives 299 were prepared by reading the benzylamine 298 with an alkyl chlorofoimate or phosgene in the absence of water [228]. 

The most cautionary examples of selective metabolisms are those in which man behaves differently from most other mammals, for herein lies one of the dangers in transferring results from laboratory animals to man. Here are some examples. The only animals that dehydrogenate quinic acid to benzoic acid are man and the Old World primates, for not even the New World primates do so. The antibacterial sulphonamide sulpha-dimethoxine is excreted by man and the primates as the N -glucuronide, whereas the common laboratory animals excrete it as the AT-acetyl-derivative (Adamson, Bridges and Williams, 1966). Other aromatic amines such as aniline and sulphanilamide are acetylated in man, and many other mammals, as well as in most species of birds, amphibia, reptiles, and fish nevertheless dogs, frogs and turtles do not perform acetylation. Further examples of different metabolic paths followed by man on the one hand and mammals on the other have been traced for amphetamine, phenylacetic acid, and 6-propylthiopurine in Section 3.4 (p. 82). 

This strategy also provides a convenient method for amination of various ester enolates with DPH Ih (Scheme 14). The amination of lithium eniminate of phenyl acetonitrile, the silyl enolate of ethyl phenylacetate and the Reformatsky reagent derived from ethyl a-bromoacetate with DPH were found to be unsuccessful. A failure of DPH for the amination of sodium enolates of S-diketones and the lithium enolate of 3-methylbutanoic acid was also reported . 

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