Pyridyl-Propionic Acid

SYNTHESIS OF (S)-AMINO-3-[3- 6-(2-METHYLPHENYL) PYRIDYLl-PROPIONIC ACID 

In an alternative process, the enz5miatic dynamic resolution of racemic amino acid 113 was also demonstrated by combining amino acid oxidase with chemical reduction. (R)-selective oxidation with Celite-immobilized (R)-amino acid oxidase from T. variabilis expressed in E. coli in combination with chemical imine reduction with borane-ammonia provided (S)-112 with a 75% process yield and 100% ee [141]. 

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Aromatization of 8-(cyano or ethoxycarbonyl)-2-oxo-2,3,4,4a,7,8-hexa-hydropyrido[l,2-A][l,2]oxazine-8-carbonitriles 12 by treatment with CS2CO3 resulted the formation of (2-pyridyl)propionic acids 13 (00OL4007). Application of other bases, e.g. DBU, NEt3, Dowex 1X8-400 ion-exchange resin afforded (2-pyridyl)propionic acids in irreproducible or considerably lower yields. 

Perhydropyrido[l,2-A][l,2]oxazines are applied as key intermediates in a stereospecific total syntheses of (-)-pumiliotoxin C and 5-e/ /-pumiliotoxin C(96JCS(P1)1113), and the marine alkaloid)—)-lepadins A, B, C (OOOL2955). (2-Pyridyl)propionic acids 13 can be regioselectively prepared via 2,3,4, 4fl,7,8-hexahydropyrido[l,2-A][l,2]oxazin-2-ones 12 (00OL4007). 

Disposition in the Body. Absorbed after oral administration accumulates in the body during chronic daily dosing. The main metabolic reactions are iV-demethylation and deamination. About 50% of a " C-labelled dose is excreted in the urine in 5 days, with 10% of the dose as unchanged brompheniramine, 11% as monodesmethylbrompheniramine, 10% as didesmethyl-brompheniramine, 4% as 3-(4-bromophenyl)-3-(2-pyridyl)-propionic acid, and 2% as its glycine conjugate other unidentified polar metabolites are also present. Less than 3% of the dose is eliminated in the faeces. Under steady-state conditions the daily excretion rate appears to be dependent on urinary pH and volume. 

Pre-infusion of FR139317 (R)2-[(R)-2-[(S)-2- [ [ 1 - (hexahydro- IH- azepinyl)] carbonyl] amino-4-methylpentanoyl] amino-3- [3-( 1-methyl- IH-indoyl)] propionyl]amino-3-(2-pyridyl)propionic acid, a selective endothelin-1 receptor antagonist (Sogabe et al. 1993), prevented post-reperfusion injury of the rat lung (Okada et al. 1995). 

S)-Amino-3-[3- 6-(2-methylphenyl)) pyridyl]-propionic acid 112 (Figure 4.31) is a key intermediate required for the synthesis of GLP-1 mimics (GLP-1 receptor modulators), potentially useful for the treatment of type-2 diabetes [139,140]. 

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