The first large-scale synthesis of MK-4305: A dual orexin receptor antagonist for the treatment of sleep disorder

Organic Process Research and Development

Volumn 15, Issue 2, 2011, Pages 367-375

  Baxter, Carl A ^a   Cleator, Ed ^a   Brands, Karel M J ^b   Edwards, John S ^a   Reamer, Robert A ^b   Sheen, Faye J ^a   Stewart, Gavin W ^a   Strotman, Neil A ^b   Wallace, Debra J ^a  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DRUG CANDIDATES; ISOLATED YIELD; LARGE SCALE SYNTHESIS; ONE-STEP PROCESS; RECEPTOR ANTAGONISTS; REDUCTIVE AMINATION; SLEEP DISORDERS; STARTING MATERIALS; SYNTHETIC ROUTES;

EID: 79952834243     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op1002853     Document Type: Article

References (10)

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7. 5, with the subsequent addition of an amine to form the 2-aminobenzoxazole. See ref 1 and Yoshida, S.; Shiokawa, S.; Kawano, K; Ito, T.; Murakami, H.; Suzuki, H.; Sato, Y. J. Med. Chem. 2005, 48, 7075-7079
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10. We initiated our screening process by taking 10 acids and screening them with a particular solvent. This was continued for a range of solvents until a suitable hit was discovered (not all acids were screened with all the solvents). Acids used: dibenzoyl- l -tartaric acid, di- p -toluoyl- l -tartaric acid, l -tartaric acid, (1 S)-(+)-10-camphorsulfonic acid, (1 R,3 S)-(+)-camphoric acid, l -malic acid, (S)-(+)-mandelic acid, (1 R,3 R,4 R,5 R)-(-)-quinic acid, deoxycholic acid, (S)-(-)-2-pyrrolidone-5-carboxylic acid. Solvents examined were: THF, acetone, EtOH, MeOH, IPA, iPAc, toluene, MeCN, DCE, water, DMF. The dibenzoyl- l -tartaric acid in THF gave the best result with a 1:1 acid/amine salt formed in 74% ee. Other solvents with the same acid gave a 2:1 acid/amine salt, which was found to be racemic.