Method for preparation of n-carboxyanhydrides

A method for the preparation of compound of formula (II),

• the method comprises a step STEP1 a step STEP2 and a STEP4,
• STEP2 is done after STEP1;
• STEP4 is done immediately after STEP2;
• STEP1 comprises a reaction REAC1, wherein compound of formula (I) is reacted with PHOS in a solvent SOLV1;
• R is selected from the group consisting of —H, —CH3, —CH2—SH, —CH2—COOH, —(CH2)2—COOH, benzyl, H,
• —CH(CH3)—CH2—CH3, —(CH2)4—NH2, —CH2—CH2—(CH3)2, —(CH2)2—S—CH3, —CH2—C(O)—NH2, —(CH2)2—C(O)—NH2, —(CH2)3—NH—C(NH)—NH2, —CH2—OH, —CH(OH)—CH3, —CH(CH3)2,
• (CH2)3—NH—C(O)—NH2, and —(CH2)3—NH2;
• any functional residue of R, which is capable of reacting with phosgene, is protected by a suitable protecting group PG;
• R1 is selected from the group consisting of H, C1-4 alkyl and benzyl;
• n is 0 or 1;
• R and R1 optionally form a pyrrolidine ring when n is 0;
• PHOS is phosgene;
• SOLV1 is selected from the group consisting of THF, 2-Me-THF, dioxan, ethyl acetate, dichlormethane, monoglyme, diglyme, triglyme, cyclopentyl methyl ether, acetonitril, and mixtures thereof;
• in STEP2 part of SOLV1 is exchanged against a solvent SOLV2 by removal of an amount of SOLV1 consisting of from 35 to 87.5 wt % of SOLV1 by distillation, the wt % being based on the weight of SOLV1, wherein in STEP2
• SOLV2 can be added before, during or after removal of the amount of SOLV1 consisting of from 35 to 87.5 wt % of SOLV1;
• SOLV2 is selected from the group consisting of
• hexyl formate, pentyl acetate, butyl propionate, propyl butyrate, ethyl valerat, methyl caproate,
• pentyl formate, butyl acetate, propyl propionate, ethyl butyrate, methyl valerate,
• butyl formate, propyl acetate, ethyl propionate, methyl butyrate, and mixtures thereof;
• and
• in STEP4 the mixture from STEP2 is mixed with a solvent SOLV4;
• SOLV4 is selected from the group consisting of pentane, hexane, cyclohexane, methylcyclohexane, heptane, octane, toluene, xylene, diethylether, MTBE, any isomers thereof, and mixtures thereof.