This compound can be prepared by two related ways: 1) The reaction of phophonoacetic acid (I) with SOCl2 at 50 C gives phosphonoacetyl chloride (II), which is condensed with diethyl aspartate (III) by means of NaOH in water affording diethyl (phosphonoacetyl)-L-aspartate (IV). Finally, this compound is hydrolyzed with LiOH or NaOH in water. 2) Compound (I) can be esterified with ethanol and dry HCl giving ethyl phosphonoacetate (V), which by reaction with hydrazine is converted into phosphonoacetyl hydrazide (VI). Finally, this compound is condensed with (III) by means of NaNO2 and HCl in DMF-water to afford (IV).
A new procedure for the synthesis of PALA has been described. The reaction of dimethyl aspartate hydrochloride (Ia) with monochloroacetic anhydride (II) in dichloromethane gives dimethyl N-chloroacetyl-L-aspartate (IIIa), which is treated with tris(trimethylsilyl)phosphite (IV) to afford dimethyl N-bis(trimethylsilyl)phosphoacetyl-L-aspartate (Va). Compound (Va) is dissolved in water and lyophilized to give dimethyl N-phosphonoacetyl-L-aspartate (VIa), which is first treated with 2N NaOH, passed through a cationic exchange resin (Dowex AG 50 W-X8) and then lyophilized to give PALA as the disodium salt. The same synthesis can also be performed from diethyl aspartate hydrochloride (Ib).