Solid phase synthesis of unsymmetrical secondary amines-application to the synthesis of arylethanolamines and arylpropanolamines

Tetrahedron Letters

Volumn 39, Issue 9, 1998, Pages 935-938

  Purandare, Ashok V ^a   Poss, Michael A ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINE; ETHANOLAMINE DERIVATIVE; PROPANOLAMINE DERIVATIVE;

ALKYLATION; ANXIETY; ARTICLE; ASTHMA; BINDING AFFINITY; DEPRESSION; DIABETES MELLITUS; DRUG ACTIVITY; HYPERTENSION; METHODOLOGY; SOLID PHASE EXTRACTION; SYNTHESIS;

EID: 0032567965     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(97)10680-3     Document Type: Article

References (13)

1. 1. a) Hermekens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron, 1997, 53, 5643-78;
2. b) Balkenhohl, F.; Bussche-Hunnfeld, C.; Lansky, A.; Zechel, C. Angew. Chem. Int. Ed. 1996, 35, 2288 and references cited therein.
3. 2. a) Conti, P.; Demont, D.; Cals, J.; Ottenheijm, H.; Leysen, D. Tetrahedron Lett. 1997, 38, 2915;
4. b) Hoekstra, W. J.; Greco, M. N.; Yabut, S. C,; Hulshizer, B. E.; Maryanoff, B. E. Tetrahedron Lett, 1997, 38, 2629;
5. c) Morphy, R.; Rankovic, Z; Rees, D. Tetrahedron Lett, 1996, 37, 3209;
6. d) Hauske, J. R.; Dorff, P. Tetrahedron Lett., 1995, 36, 1589.
7. 3. a) In a 1995 survey, thirteen of the top 200 drugs ranked by prescription volume were ethanolamine based compounds (source: Pharmacy Times, April 1996);
8. b) Hieble, J. P.; Bond, R. A. Trends in Pharmacological Sciences, 1994, 75, 397;
9. c) Hieble, J. P.; Ruffolo, R. R..; Ruffolo, R. R. J. Med. Chem. 1995, 38, 3415;
10. d) Ruffolo, R. R.; Ruffolo, R. R.; Hieble, J. P. J. Med. Chem. 1995, 38, 3681.
11. 4. Look, G. C.; Murphy, M. M.; Campbell, D. A.; Gallop, M. A. Tetrahedron Lett, 1995, 36, 2937.
12. 5. General Experimental Procedure for 9: A suspension of commercially available Fmoc-Knorr resin (150 mg, 0.132 mmol) in DMF-piperidine (1:1) was vortexed for 30 minutes. The solvent was drained and the resin was washed with DMF (3 × 5 mL) and then resuspended in a mixture of DMF-trimethyl orthoformate (5 mL, 1:1). 4-Fluorobenzaldehyde (20 mg, 0.16 mmol) and acetic acid (10 μL) were added and the resin was allowed to vortex for 1 hour. Sodium triacetoxyborohydride (41 mg, 0.2 mmol) was added and the resulting suspension was vortexed overnight. The resin was successively washed with DMF (3 × 5 mL), dichloromethane (3 × 5 mL) and finally with methanol to afford resin 2. 2-Chloroacetophenone (60 mg, 0.4 mmol) was added to resin 2 suspended in a mixture of DMF-acetone (8 mL, 1:1). The reaction mixture was heated at 45°C for 10 hours. Thereupon the resin was washed with DMF (3 × 5 mL) and THF (2 × 5 mL) to afford resin 5. Sodium borohydride (10 mg, 0.26 mmol) was added to resin 5 previously swollen in a mixture of THF-ethanol (8 mL, 1:1) and the mixture was vortexed for 4 hours. The resin was successively washed with THF (2 × 5 mL), 10% acetic acid solution in THF (3 × 5 mL), THF (2 × 5 mL) and finally methanol (2 × 5 mL), to give resin 7. Resin 7 was shaken in a mixture of TFA-dichloromethane (5 mL, 1:1) for 3 hours and the resulting solution was filtered and concentrated to give a pale brown colored residue. The residue was reconstituted in methanol and concentrated to give compound 9 as the trifluoroacetate salt (21.3 mg) in 45% overall yield (from Knorr resin).
13. 13C NMR.