Ethyl acetamidomalonate

A large number of a-amino acids have been prepared by various modifications of the Sorensen m.ethod ° in which acylaminornalonic esters are alkylated and degraded. Ethyl acetamidomalonate (R = CHjethyl benzamidomalonate (R = C Hs), and ethyl formamidomalonate (R = H) have been used. The acetyl group is more easily introduced and removed than the benzoyl group. ... 

A soln. of acrolein in benzene dropped at a moderate rate into a suspension of ethyl acetamidomalonate in benzene containing a catalytic amount of Na-methoxide, stirred 2 hrs. longer, and isolated as the phenylhydrazone —y-acetamido-y,y-dicarbethoxy-butyraldehyde phenvlhydrazone. Y 87%. (F. e. s. O. A. Moe and D. T. Warner, Am. Soc. 70, 2763 (1948) 71, 2586 (1949).)... 

Method Five, Albertson and Archer (46). Ethyl 2-acetamido-2-car-bethoxy-3-phenylpropionate (A) is prepared in 90% yield from benzyl chloride and ethyl acetamidomalonate. DL-Phenylalanine is prepared in 65% yield by HBr or NaOH-HCl hydrolysis of (A). The over-all yield is 58%. (Comparable syntheses of phenylalanine from benzyl chloride and diethyl aminomalonate (144, 526) or diethyl benzamido-malonate (660) have been reported). 

Method One, Snyder et al. (410, 741). Ethyl acetamidomalonate -)- gramine methiodide sodium - ethyl o-acetamido-o-carbethoxy-j3-(3-indole)-propionate (A) a-acetamido-a-carbmgr-jS-(3-indole)-propionic acid -> N-acetyltryptophan -> tryptophan (81% yield based on (A)]. 

Acrolein can be used as starting material for tryptophan synthesis 227, 228, 239). The Michael-type condensation between acrolein (12) and ethyl acetamidomalonate (13) gives y-acetamido-y,y-dicarbethoxy-butyraldehyde (14), whose phenyhydrazone by the Fischer indole synthesis gives D,L-tryptophan. Of the hitherto reported methods, the synthetic route employed by Komachiya et al. 227) appears most suitable for the industrial synthesis of D,L-tryptophan. 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

In a deceivingly simple process apparently involving a butatriene intermediate, a one-pot preparation of ethyl 5-methylpyrrole-2-carboxylate (6) from diethyl acetamidomalonate (4) and l,4-dichloro-2-butyne (5) has been described <96JOC9068>. 

Sodium salt of diethyl acetamidomalonate 480 reacts with ethyl 2,3-butadienoate in the presence of a catalytic amount of EtONa to afford /fy-unsaturated enoate 481, which can be easily decarboxylated leading to /3-methyleneglutamic acid hydrochloride 482 [220],... 

From diethyl acetamidomalonate and 2-(4-fluorophenoxy)ethyl bromide a spiro-benzopyranyl amino acid 101 could be prepared (88TL5493). 

Due to the laborious multiple steps of this synthesis and the correspondingly low yields, an alternative synthetic approach based on alkylation of the acetamidomalonate 10 with ethyl 6-bromohexanoate (9) giving the racemic a-aminosuberic acid 12 after deacetylation of the amino group in 11 and decarboxylation, as shown in Scheme 5, is significantly more efficient. ... 

American workers needed to prepare the bis-amino acid 1 and adopted a literature procedure in which two equivalents of diethyl acetamidomalonate were to be alkylated with one equivalent of l,4-dichloro-2-butyne using two equivalents of sodium ethoxide in hot ethanol. Hydrolysis and decarboxylation of the dialkylated malonate would then give 1. This alkylation reaction was carried out, but ten equivalents of sodium ethoxide were used rather than two. This resulted in formation of ethyl 5-methylpyrrole-2-carboxylate in ca. 40% yield. Further study showed that the reaction to produce the pyrrole required equimolar amounts of the acetamidomalonate and the dichlorobutyne, excess of sodium ethoxide, and heating. No pyrrole was formed at room temperature. 

Related Reagents. (2S,4S)-3-Benzoyl-2-r-butyl-4-methyl-l,3-oxazolidin-5-one t-Butyl 2-t-Butyl-3-methyl-4-oxo-l-imi-dazolidinecarboxylate (/ )-2-t-Butyl-6-methyl-4//-l,3-dioxin-4-one (/ ,/ )-2-t-Buty 1-5-methyl-l,3-dioxolan-4-one Diethyl Acetamidomalonate A/-(Diphenylmethylene)aminoacetonitrile Ethyl A/-(Diphenylmethylene)glycinate Ethyl Isocyanoacetate Methyl A/-Benzylidenealaninate (/ )-Methyl 2-t-Butyl-3(2iiO-oxazolecarboxylate. 

Compound (VIII.98), a folic acid analogue with a y-fluoro substituent in the side-chain was described first by Alekseeva e/ al. [281] and several years later by Bergmann and Chun-Hsu [282]. The synthesis of (VIII.98), as mixture of threo and erythro isomers, was achieved via the Waller method from V-(4-ami-nobenzoyl)-y-fluoroglutamic acid, 2,4,5-triamino-6(lif)-pyrimidinone, and 2,3-dibromopropionaldehyde, but the yield was low (5.6%). y-Fluoroglutamic acid, as a mixture of D- and L-enantiomers, was prepared from diethyl 2-fluoromalonate by condensation with ethyl 2-acetamidoacrylate followed by hydrolysis and decarboxylation in refluxing 12 M HCl, or from ethyl 3-chloro-2-hydroxypropanoate by a sequence consisting of (i) 0-t-butylation with CH2 = C(CH3)2, (ii) condensation with diethyl 2-acetamidomalonate, (hi)... 

Norvaline. 2-Aminmrateric acid a-aminovaleric acid 2-aminopentanoic acid. C-H,NO, mol wt 117 15. C 51.26%, H 9.47%, N 11.96%, 6 27.32%. CH,(CH,),CH-(NHj)COOH. Prepd by treating butyraldehyde ammonia with HCN and HCh Slimmer, Bee. 35. 404 (1902) from 2-acetylvaleric acid ethyl ester Hamlin, Hartung, J. BioL Chem. 145, 349 (1942) from acetamidomalonic acid diethyl... 

A soln. of diethyl acetamidomalonate in dimethylformamide added dropwise at 0-5° to a stirred 64%-NaH-oil dispersion in dimethylformamide, stirring continued 1 hr. at the same temp., then added gradually with ice-cooling to a soln. of l-tosyl-5-acetoxymethylimidazole in dimethylformamide, and stirring continued 2 hrs. at room temp. ethyl a-ethoxycarbonyl-a-acetylamino-/ -(l-tosylimidazole-5)-propionate. Y 80%. K. Matsumoto et al., Agr. Biol. Chem. (Tokyo) 38, 1097 (1974). 

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