反应详情

温度

50 °C

3.50 kg (10.91 mol) of methyl-[(1S,3R)-3-(4-methyl-piperazin-1-yl)cyclohexyl]-amine tri-hydrochloride (F) and 4.24 kg (12.00 mol) of the sodium salt of {2-[(4-methoxy-2,6-dimethyl-benzenesulphonyl)-methyl-amino]-ethoxy}-acetic acid (E) were suspended in 17.5 L of THF and heated to 50±5° C. Then 21.43 kg (38.19 mol) potassium tert. butoxide solution in tetrahydrofuran, 5.0 L of tetrahydrofuran, 13.89 kg (83.97 mol) of 50% propanephosphonic anhydride in ethyl acetate and a further 5.0 L of tetrahydrofuran were metered in successively and the reaction mixture was stirred for approx. 1 hour at 50±5° C. After the reaction had ended 17.5 L toluene and 19.5 L water were added and the pH of the aqueous phase was adjusted to less than 2.5 with hydrochloric acid (30%). The aqueous phase was separated off, diluted with 2.0 L water and combined at 50° C. with 42 L of methylisobutylketone and a mixture of 4.45 kg (55.65 mol) sodium hydroxide solution (50%, industrial grade) and 3.5 L of water. After approx. 5 minutes' stirring at 50° C. the aqueous phase was separated off and 28.0 L solvent were distilled off in vacuo. The cloudy residue was filtered at 60° C. and the filtrate was combined with 14.0 L of methylisobutylketone. Then the solvent was eliminated completely in vacuo and product (G) was isolated.

1. additionwere added
2. customThe aqueous phase was separated off
3. additiondiluted with 2.0 L water
4. customcombined at 50° C. with 42 L of methylisobutylketone
5. stirringAfter approx. 5 minutes' stirring at 50° C. the aqueous phase
6. customwas separated off
7. distillation28.0 L solvent were distilled off in vacuo
8. filtrationThe cloudy residue was filtered at 60° C.