Ethyl N-(2,3-dichloro-6-aminobenzyl)glcycine synthesis

Yield:-

Reaction Conditions:

Stage #1: N-(2,3-dichloro-6-nitrobenzyl)glycine ethyl ester hydrochloridewith hydrogenchloride;tin(ll) chloride in water at 15 - 45; for 3 h;
Stage #2: with potassium carbonate in water at 0 - 5; pH=8.0 - 9.0;

Steps:

3.a

Example 3; Preparation of Anagrelide , a compound of formula (II); a) Preparation of Ethyl-5,6-dichloro-3,4-dihydro-2[lH]-imino quinazolin-3-acetate hydrobromide; A solution of stannous chloride dihydrate (1850 gms) in concentrated HCl (6.7 liters ) was added slowly to a cooled solution of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride (595gms) in concentrated HCl (5.15 liters) maintaining temperature 15-20⁰C over a period of 2 hours. The contents were heated slowly to 40-45⁰C and stirred for 1 hour at 40-45⁰C. After completion of reaction, the contents were cooled to 15-2O⁰C, maintained for 15 minutes and filtered.The solids thus obtained were suspended in water (2.9 liters), adjusted the pH of the reaction mass to 8.0-9.0 using potassium carbonate solution (prepared by dissolving 376 gms of potassium carbonate in 4.25 liters of water) at 0-5⁰C, extracted into toluene (3.0 liters><3), dried over sodium sulphate and clarified.To the clear toluene layer, added Cyanogen bromide solution (prepared by dissolving 222 gms of cyanogen bromide in 655 ml of toluene) in 30 minutes maintaining temperature 15-20⁰C and stirred at 25-30⁰C for 2 hours. The contents were heated slowly to 105-110⁰C and maintained for 16 hours at 105-110⁰C. After completion of reaction, the mass was cooled to 15-2O⁰C and stirred for 45 minutes. Filtered the material, washed with chilled toluene (1.3 liters). The material was slurried in toluene (470 ml) at 15-20⁰C for 1 hour, filtered, washed with cold toluene (160 ml) and dried under vacuum at 50-60⁰C for 8 hours to give the title compound (445 gms ).

References:

WO2008/96145,2008,A1 Location in patent:Page/Page column 13-14