A convenient method for the N-acylation and esterification of hindered amino acids: Synthesis of ultra short acting opioid agonist, remifentanil

Synlett

Volumn , Issue 12, 1999, Pages 1923-1924

  Coleman, Mark J ^a   Goodyear, Michael D ^a   Latham, David W S ^a   Whitehead, Andrew J ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

Acylation; Amino acids; Esterification

Indexed keywords

AMINO ACID; OPIATE AGONIST; REMIFENTANIL;

ACYLATION; ARTICLE; DRUG SYNTHESIS; ESTERIFICATION; REACTION ANALYSIS; X RAY ANALYSIS;

EID: 0032714942     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-1999-2978     Document Type: Article

References (9)

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8. General procedure for the preparation of N-acylamino esters of type 7: Triethylamine (0.3 mol, 41.8 mL) was added slowly to a stirred suspension of the acid 5 (0.1 mol, 34.7 g) and propionic anhydride (0.7 mol, 89.8 mL) in ethyl acetate (260 mL) at reflux and the resulting solution was heated at reflux for 1 h. The reaction mixture was cooled to 70°C, methanol (70 mL) added, the reaction heated at reflux for a further 2 h, cooled to room temperature and then basified with 5 M aqueous sodium hydroxide. The biphasic mixture was separated and the aqueous extracted with ethyl acetate, the combined ethyl acetate solution was washed with 2M aqueous sodium hydroxide and water. Water was then added followed by aqueous phosphoric acid (2.5 M) until the pH of the aqueous reached 6. The layers were separated and a solution of oxalic acid dihydrate (0.1 mol, 12.6 g) in methanol (34.7 mL) was added to the organic layer. The resulting solid was isolated by filtration and washed with ethyl acetate and dried in vacuo at 40°C to afford the product 7b (43.5 g, 92%).
9. Ketcha D. M.; Abou-Gharbia M.; Smith F. X. and Swern D. Tetrahedron Lett. 1983, 24, 2811.