反应详情

N-4-Cyanobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid methyl ester (80 mg, 0.16 mmol) was dissolved in pyridine (10 ml). To the resulting solution was added triethylamine (1 ml) and the mixture was saturated with hydrogen sulfide gas. The reaction vessel was sealed and the reaction mixture was stirred at room temperature overnight. The pyridine was distilled off and the volatile products were removed by two cycles of toluene azeotropy. The residue was dissolved in acetone (15 ml) and methyl iodide (1 ml) was added thereto, followed by refluxing for 30 minutes. The solvent was distilled off and the residue was dissolved in methanol (10 ml). To the obtained solution was added ammonium acetate (100 mg) and the mixture was refluxed for 2 hours. After the solvent was distilled off, the residue was dissolved in chloroform, washed with a saturated aqueous solution of NaCl and dried over anhydrous sodium sulfate. The obtained crude N-4-amidinobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid methyl ester (18 mg) was dissolved in an 50% aqueous methanol solution (10 ml). To the resulting solution was added a 2N aqueous solution of lithium hydroxide (3 ml) at room temperature and the mixture was stirred for 15 minutes. After the reaction solution was neutralized with 3N HCl to pH 7, the solvents were distilled off and the residue was dissolved in a 1N aqueous solution of acetic acid. The resulting solution was purified with a HPLC to yield N-(N-4-amidinobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid (3.5 mg, 20.0%).

1. customThe reaction vessel was sealed
2. distillationThe pyridine was distilled off
3. customthe volatile products were removed by two cycles of toluene azeotropy
4. dissolutionThe residue was dissolved in acetone (15 ml)
5. additionmethyl iodide (1 ml) was added
6. temperatureby refluxing for 30 minutes
7. distillationThe solvent was distilled off
8. dissolutionthe residue was dissolved in methanol (10 ml)
9. additionTo the obtained solution was added ammonium acetate (100 mg)
10. temperaturethe mixture was refluxed for 2 hours
11. distillationAfter the solvent was distilled off
12. dissolutionthe residue was dissolved in chloroform
13. washwashed with a saturated aqueous solution of NaCl
14. dry with materialdried over anhydrous sodium sulfate
15. customThe obtained crude N-4-amidinobenzoyl-β-m-chlorophenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid methyl ester (18 mg)
16. stirringthe mixture was stirred for 15 minutes
17. distillationthe solvents were distilled off
18. dissolutionthe residue was dissolved in a 1N aqueous solution of acetic acid
19. customThe resulting solution was purified with a HPLC