An improved method of amide synthesis using acyl chlorides

Tetrahedron Letters

Volumn 50, Issue 24, 2009, Pages 2964-2966

  Zhang, Li ^a   Wang, Xiao jun ^a   Wang, Jing ^a   Grinberg, Nelu ^a   Krishnamurthy, DhileepKumar ^a   Senanayake, Chris H ^a  

^a BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDE; CHLORIDE;

ARTICLE; CHEMICAL REACTION; CHEMICAL STRUCTURE; COLUMN CHROMATOGRAPHY; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HYDROLYSIS; RACEMIZATION; SYNTHESIS;

EID: 65249158549     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2009.03.220     Document Type: Article

References (13)

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8. General procedure for coupling with amines (Table 3, 9a-9d). A solution of acyl chloride (2 mmol) in THF (4 mL) was cooled to 0 °C under nitrogen. Potassium phosphate (530 mg, 2.5 mmol) was added in one portion followed by the addition of amine 8 (2 mmol). The mixture was allowed to react for 1 h at rt. The reaction was quenched with water (6 mL) and EtOAc (2 mL). The organic layer was evaporated under vacuum. The crude product was purified either by crystallization or by silica gel column chromatography.
9. General procedure for coupling with amino acids (Table 4, 9e-9h). A solution of acyl chloride (2 mmol) in THF (4 mL) was cooled to 0 °C under nitrogen. Potassium phosphate (1.06 g, 5.0 mmol) was added in one portion followed by the addition of amino acid 8 (2 mmol). The mixture was allowed to react for 12 h at rt. The reaction was quenched with water (10 mL) and EtOAc (4 mL). The organic layer was discarded. The pH of aqueous layer was adjusted to 2 by 2 N HCl. The product was extracted with EtOAc (10 mL) and washed with water (6 mL). The organic layer was evaporated under vacuum. The crude product was purified either by crystallization or by silica gel column chromatography.
10. Fischer E. Chem. Ber. (1906) 3988
11. Danger G., Boiteau L., Cottet H., and Pascal R. J. Am. Chem. Soc. 128 (2006) 7412
12. Scale-up procedure for coupling with amino acids (Table 4, 9h). A solution of 2-(naphthalen-1-yloxy)-acetyl chloride 7 h (463 g, 2.10 mol) in THF (6 L) was cooled to 0 °C under nitrogen. d,l-Phenylglycine 8h (302 g, 2.00 mol) was added followed by potassium phosphate (929 g, 4.37 mol). The mixture was allowed to react for 12 h at rt. The reaction was quenched with water (4 L). Most of the THF (5 L) was distilled and MeCN (6 L) was added. The pH was adjusted to 2-3 by 1 N HCl (4.4 L) and the reaction mixture was filtered. The cake was washed with 1:1 MeCN/water (4 L) to afford 9h as a white solid (576 g, 86% yield).
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