The reaction of ethyl alpha-bromopropionate (I) with triethyl phosphite (II) by heating at 160-90 C gives triethyl alpha-phosphonopropionate (III) (1), which by reaction with hydrazine is converted into the corresponding hydrazide (IV). The nitrosation of (IV) with NaNO2 and HCl affords the azide (V), which spontaneously evolves N2 yielding the isocyanate (VI). The hydrolysis of (VI) with ethanol gives the carbamate (VII), which is hydrolyzed with concentrated aqueous HCl affording 1-aminoethylphosphonic acid (VIII) (2). The protection of the NH2 group with benzyl chloroformate (IX) gives the N-carbobenzoxy derivative (X), which is esterified with triethyl orthoformate to the protected ester (XI). Hydrogenolysis of (XI) with H2 over Pd/C in methanol yields diethyl 1-aminoethylphosphonate (XII), which is condensed with N-carbobenzoxy-L-alanine (XIII) by means of DCC in CH2Cl2 giving diethyl N-(carbobenzoxy-L-alanyl)-1-aminoethylphosphonic acid (XIV). Finally this compound is hydrolyzed with HBr in acetic acid (3-6).

The reaction of ethyl alpha-bromopropionate (I) with triethyl phosphite (II) by heating at 160-90 C gives triethyl alpha-phosphonopropionate (III) (1), which by reaction with hydrazine is converted into the corresponding hydrazide (IV). The nitrosation of (IV) with NaNO2 and HCl affords the azide (V), which spontaneously evolves N2 yielding the isocyanate (VI). The hydrolysis of (VI) with ethanol gives the carbamate (VII), which is hydrolyzed with concentrated aqueous HCl affording 1-aminoethylphosphonic acid (VIII) (2). The protection of the NH2 group with benzyl chloroformate (IX) gives the N-carbobenzoxy derivative (X), which is esterified with triethyl orthoformate to the protected ester (XI). Hydrogenolysis of (XI) with H2 over Pd/C in methanol yields diethyl 1-aminoethylphosphonate (XII), which is condensed with N-carbobenzoxy-L-alanine (XIII) by means of DCC in CH2Cl2 giving diethyl N-(carbobenzoxy-L-alanyl)-1-aminoethylphosphonic acid (XIV). Finally this compound is hydrolyzed with HBr in acetic acid (3-6).

The reaction of ethyl alpha-bromopropionate (I) with triethyl phosphite (II) by heating at 160-90 C gives triethyl alpha-phosphonopropionate (III) (1), which by reaction with hydrazine is converted into the corresponding hydrazide (IV). The nitrosation of (IV) with NaNO2 and HCl affords the azide (V), which spontaneously evolves N2 yielding the isocyanate (VI). The hydrolysis of (VI) with ethanol gives the carbamate (VII), which is hydrolyzed with concentrated aqueous HCl affording 1-aminoethylphosphonic acid (VIII) (2). The protection of the NH2 group with benzyl chloroformate (IX) gives the N-carbobenzoxy derivative (X), which is esterified with triethyl orthoformate to the protected ester (XI). Hydrogenolysis of (XI) with H2 over Pd/C in methanol yields diethyl 1-aminoethylphosphonate (XII), which is condensed with N-carbobenzoxy-L-alanine (XIII) by means of DCC in CH2Cl2 giving diethyl N-(carbobenzoxy-L-alanyl)-1-aminoethylphosphonic acid (XIV). Finally this compound is hydrolyzed with HBr in acetic acid (3-6).

A new synthesis of alafosfalin has been reported : The condensation of N-carbobenzoxy-L-alanine (I) with diphenyl 1-aminoethylphosphonate (II) gives the protected phenyl ester (III), which is transesterified with methanol - KF - crown ether to the corresponding protected dimethyl ester (IV). Finally this compound is deprotected and hydrolyzed with HBr in acetic acid.

The reaction of ethyl alpha-bromopropionate (I) with triethyl phosphite (II) by heating at 160-90 C gives triethyl alpha-phosphonopropionate (III) (1), which by reaction with hydrazine is converted into the corresponding hydrazide (IV). The nitrosation of (IV) with NaNO2 and HCl affords the azide (V), which spontaneously evolves N2 yielding the isocyanate (VI). The hydrolysis of (VI) with ethanol gives the carbamate (VII), which is hydrolyzed with concentrated aqueous HCl affording 1-aminoethylphosphonic acid (VIII) (2). The protection of the NH2 group with benzyl chloroformate (IX) gives the N-carbobenzoxy derivative (X), which is esterified with triethyl orthoformate to the protected ester (XI). Hydrogenolysis of (XI) with H2 over Pd/C in methanol yields diethyl 1-aminoethylphosphonate (XII), which is condensed with N-carbobenzoxy-L-alanine (XIII) by means of DCC in CH2Cl2 giving diethyl N-(carbobenzoxy-L-alanyl)-1-aminoethylphosphonic acid (XIV). Finally this compound is hydrolyzed with HBr in acetic acid (3-6).

The reaction of ethyl alpha-bromopropionate (I) with triethyl phosphite (II) by heating at 160-90 C gives triethyl alpha-phosphonopropionate (III) (1), which by reaction with hydrazine is converted into the corresponding hydrazide (IV). The nitrosation of (IV) with NaNO2 and HCl affords the azide (V), which spontaneously evolves N2 yielding the isocyanate (VI). The hydrolysis of (VI) with ethanol gives the carbamate (VII), which is hydrolyzed with concentrated aqueous HCl affording 1-aminoethylphosphonic acid (VIII) (2). The protection of the NH2 group with benzyl chloroformate (IX) gives the N-carbobenzoxy derivative (X), which is esterified with triethyl orthoformate to the protected ester (XI). Hydrogenolysis of (XI) with H2 over Pd/C in methanol yields diethyl 1-aminoethylphosphonate (XII), which is condensed with N-carbobenzoxy-L-alanine (XIII) by means of DCC in CH2Cl2 giving diethyl N-(carbobenzoxy-L-alanyl)-1-aminoethylphosphonic acid (XIV). Finally this compound is hydrolyzed with HBr in acetic acid (3-6).

The reaction of ethyl alpha-bromopropionate (I) with triethyl phosphite (II) by heating at 160-90 C gives triethyl alpha-phosphonopropionate (III) (1), which by reaction with hydrazine is converted into the corresponding hydrazide (IV). The nitrosation of (IV) with NaNO2 and HCl affords the azide (V), which spontaneously evolves N2 yielding the isocyanate (VI). The hydrolysis of (VI) with ethanol gives the carbamate (VII), which is hydrolyzed with concentrated aqueous HCl affording 1-aminoethylphosphonic acid (VIII) (2). The protection of the NH2 group with benzyl chloroformate (IX) gives the N-carbobenzoxy derivative (X), which is esterified with triethyl orthoformate to the protected ester (XI). Hydrogenolysis of (XI) with H2 over Pd/C in methanol yields diethyl 1-aminoethylphosphonate (XII), which is condensed with N-carbobenzoxy-L-alanine (XIII) by means of DCC in CH2Cl2 giving diethyl N-(carbobenzoxy-L-alanyl)-1-aminoethylphosphonic acid (XIV). Finally this compound is hydrolyzed with HBr in acetic acid (3-6).

The reaction of ethyl alpha-bromopropionate (I) with triethyl phosphite (II) by heating at 160-90 C gives triethyl alpha-phosphonopropionate (III) (1), which by reaction with hydrazine is converted into the corresponding hydrazide (IV). The nitrosation of (IV) with NaNO2 and HCl affords the azide (V), which spontaneously evolves N2 yielding the isocyanate (VI). The hydrolysis of (VI) with ethanol gives the carbamate (VII), which is hydrolyzed with concentrated aqueous HCl affording 1-aminoethylphosphonic acid (VIII) (2). The protection of the NH2 group with benzyl chloroformate (IX) gives the N-carbobenzoxy derivative (X), which is esterified with triethyl orthoformate to the protected ester (XI). Hydrogenolysis of (XI) with H2 over Pd/C in methanol yields diethyl 1-aminoethylphosphonate (XII), which is condensed with N-carbobenzoxy-L-alanine (XIII) by means of DCC in CH2Cl2 giving diethyl N-(carbobenzoxy-L-alanyl)-1-aminoethylphosphonic acid (XIV). Finally this compound is hydrolyzed with HBr in acetic acid (3-6).