Amino acid amides

The industrial process for preparing the reagent usually permits a little hydrolysis to occur, and the product may contain a little free calcium hydroxide or basic chloride. It cannot therefore be employed for drying acids or acidic liquids. Calcium chloride combines with alcohols, phenols, amines, amino-acids, amides, ketones, and some aldehydes and esters, and thus cannot be used with these classes of compounds. 

Almost all actinomycins have the same chromophore, a planar phenoxa2inone dicarboxyUc acid called actinocin. In dactinomycin, the stmcture of which is shown in Figure 12, the two pendent pentapeptide lactones are identical, but in other actinomycins these lactones may be different. In other actinomycins the first amino acid, amide linked with actinocin, is usually L-threonine, as in dactinomycin the second position is sometimes D-aHo-isoleucine instead of D-valine the third position may be sarcosine or oxoproline the fourth position is sarcosine and the fifth position is sometimes /V-methyl isoleucine instead of /V-methylvaline. The lactone ring is always present. 

With monoamines, the oxazolones give the normal ring-opened products, A-TFA amino acid amides, but with aniline both forms... 

As expected from the design of the experiment, the HPLC column packed with CSP 14 containing all 36 members of the library with tt-basic substituents separated 7t-acid substituted amino acid amides. Although encouraging since it suggested the presence of at least one useful selector, this result did not reveal which of the numerous selectors on CSP 14 was the most powerful one. Therefore, a deconvolution process involving the preparation of series of beads with smaller numbers of attached selectors was used. The approach is schematically outlined in Fig. 3-17. 

The aqueous layer is evaporated in vacuo to yield almost quantitatively the amino acid amides 2 as the hydrochlorides. The hydrochlorides are treated with 10 mL of 6 N HCl at 80 CC until they arc completely hydrolyzed (TLC monitoring, about 24 to 48 h). After evaporation in vacuo the remaining crystalline... 

Asano et al. have developed an approach for the synthesis of D-amino acids through DKR using a two-enzyme system [55]. They had previously reported the discovery of new D-stereospecific hydrolases that can be applied to KR of racemic amino acid amides to yield D-amino acids. Combination of a D-stereospedfic hydrolase with an amino acid amide racemase allows performing DKR of i-amino acid amides yielding enantiomerically pure D-amino acids in excellent yields (Figure 4.29). 

Racemic a-amino amides and a-hydroxy amides have been hydrolyzed enantio-selectively by amidases. Both L-selective and o-selective amidases are known. For example, a purified L-selective amidase from Ochrobactrum anthropi combines a very broad substrate specificity with a high enantioselectivity on a-hydrogen and a,a-disubstituted a-amino acid amides, a-hydroxyacid amides, and a-N-hydroxya-mino acid amides [102]. A racemase (a-amino-e-caprolactam racemase, EC 5.1.1.15) converts the o-aminopeptidase-catalyzed hydrolysis of a-amino acid amides into a DKR (Figure 6.38) [103]. 

Figure 6.38 Dynamic kinetic resolution of amino acid amides.

Amines, amino acids, amides [1, 2] e.g. chloramphenicol, creatine, adenine, guanine histidine, phenylalanine, sphingosine... 

Knobler Y, Bittner S, Frankel M (1964) Reaction of N-carboxy-alpha-amino-acid anhydrides with hydrochlorides of hydroxylamine O-alkylhydroxylamines + amines syntheses of amino-hydroxamic acids amido-oxy-peptides + alpha-amino-acid amides. J Chem Soc 3941... 

Another method for the synthesis of amino-acid amides entails the conversion of N-( 1 -benzotriazolylcarbonyl) amino acids with amines in anhydrous or aqueous systems C1101... 

Asano, Y. and Yamaguchi, S. (2005) Dynamic kinetic resolution of amino acid amide catalyzed by D-aminopeptidase and a-amino-e-caprolactam racemase. Journal of the American Chemical Society, 127 (21), 7696-7697. 

Boesten, W.H.J., Raemakers-Franken, PC., Sonke, T. et al. (2003) Protein and cDNA sequences of -//- -amino acid amide racemases cloned from Ochrobactrum anthropi and Arthrobacter nicotianae, W02003106691. 

In another variant of these intramolecular 1,3-dipolar cycloadditions, the alkyne-containing amino acid amide 183, when reacted with acetic anhydride, produces a zwitterionic thiazolo-oxazolium intermediate, which may then react intramolecularly with the dipolarophile and give the triheterocycle 184 < 1999J(P 1) 1219, 2002JOC4045> (Equation 18). The benzo-fused analogue 185 is obtained similarly (Equation 19). 

The solvent-free preparation of 1,2,3-trisubstituted imidazolidin-4-ones from aldehydes and N-substituted a-amino acid amides has been reported by Pospisil and Potacek (Scheme 6.202) [365], The general procedure simply involved heating equimolar mixtures of the aldehyde and amine building blocks under open-vessel micro-wave irradiation for 5 min at 200 °C. After cooling to room temperature, the imida-zolidin-4-one products were purified by flash chromatography. 

A method for the preparation of 1,3,2-diazaphospholidine heterocydes has been described by Deng and Chen (Scheme 6.225) [402], The authors found that treating hindered 1,2-diamino substrates such as a-amino acid amides with tris(diethylami-no)phosphine as reagent/solvent under open-vessel microwave conditions at 250 °C for 1 min furnished a trivalent phosphorus intermediate. Subsequent thiation of this intermediate with elemental sulfur in refluxing benzene provided the target l,3,2-diazaphospholidin-4-ones in good overall yields. The yields were much improved compared to those achieved by standard thermal methods. 

Scheme 25.2 Hydrogenation of the /tdehydro amino acid amide intermediate for MK-0431.

Efforts to find potent and selective DPP-4 inhibitors in the a-amino acid amide series were made in parallel with those in the (3-amino acid amides series. The structural origin of the earliest P-amino acid amide DPP-4 inhibitors traces back to two Merck HTS hits proline derivative 25 and piperazine derivative 26. These two screening leads were further progressed to P-amino acid amide DPP-4 inhibitors incorporating thiazolidine, proline and piperazine amide moieties (Figure 17.5). 

Incorporation of the P-amino acid amide from 25 into piperazine hit 26 improved DPP-4 inhibition by more than 80-fold and led to the discovery of 32 (Table 17.5) [46], The 2-fluorophenyl effect on DPP-4 potency was again observed with compound 33 however, this compound showed very high clearance and no oral bioavailability in the rat. More simplified truncated compounds 34 and 35 showed decreased DPP-4 potency by 10-fold compared to 33, and the removal of the benzyl group resulted in a more significant loss of DPP-4 activity (36). Unfortunately, while 34 showed good... 

To improve DPP-4 activity as well as pharmacokinetic properties, the effects of substituents on triazolopiperazine moieties were examined (Table 17.7) [48], Aryl and heteroaryl substituents were found to be as effective as alkyl substituents at improving DPP-4 activity. Unlike most ofthe previous (1-amino acid amide analogues in this series, these analogues (e.g. 43 and 44) exhibited unacceptable DPP-8 and hERG activities (IC50 S — 1-4 pM). The effects of perfluoroalkyl substituents were... 

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