Synthesis of the orally active spiroindoline-based Growth Hormone Secretagogue, MK-677

Tetrahedron

Volumn 53, Issue 32, 1997, Pages 10983-10992

  Maligres, Peter E ^a   Houpis, Ioannis ^a   Rossen, Kai ^a   Molina, Audrey ^a   Sager, Jess ^a   Upadhyay, Veena ^a   Wells, Kenneth M ^a   Reamer, Robert A ^a   Lynch, Joseph E ^a   Askin, David ^a   Volante, R P ^a   Reider, Paul J ^a   Houghton, Peter ^b  

^a MERCK RESEARCH LABORATORIES   (United States)

^b Merck Sharp & Dohme Limited   (United Kingdom)

Author keywords

Fischer indole; Growth hormone secretagogue; MK 677; Rosenmund; Spiroindoline

Indexed keywords

IBUTAMOREN; INDOLE DERIVATIVE; SPIRO COMPOUND; UNCLASSIFIED DRUG;

ARTICLE; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IN VITRO STUDY; INFRARED SPECTROPHOTOMETRY; MASS SPECTROMETRY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PRIORITY JOURNAL; REACTION ANALYSIS;

EID: 0030851241     PISSN: 00404020     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4020(97)00359-1     Document Type: Article

References (38)

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22. Thiophenol gave similar results while other catalyst poisons such as elemental sulfur, thiourea, t-dodecanethiol and quinoline gave less satisfactory results. The addition of thioanisole up to 0.1 mol% did not substantially decrease the rate of hydrogenation of 5 to 6.
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25. 8-toluene.
26. Varying amounts (1-20%) of dimeric product 7 were formed. Both 6 and 7 are readily oxidized by atmospheric oxygen to the corresponding acids.
27. 3, PhCl-MeCN, and 1,2-dichlorobenzene-MeCN also gave satisfactory results.
28. 5.
29. Spiroindolenine 8 was found to be in equilibrium with its cyclic trimer T, with monomeric 8 being favored under acidic conditions, (a) Nomura, Y.; Bando, T.; Takeuchi, Y.; Tomoda, S. Bull. Chem. Soc. Jpn. 1983, 56, 3199-3120,
30. 3CN) δ 84.5, 83.2, 85.3. (formula presented)
31. 3N, 1.2 mL/min flow at 48°C with detection at 210 nm, retention time: N-Ms-N'-benzyl-spiroindoline = 13.4. The formation of the N-benzylated byproduct could be readily circumvented by thorough agitation during the hydrogenation. The amine 11 could be crystallized as its free base from EtOAc-MTBE-hexane (82%) or as its HCl salt from MeOH-EtOAc (86%).
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36. 2NH salt.
37. 2 as derivative B. Retention times: 4 = 2.1 min, A = 11.0 min, toluene = 12.1 min, B = 12.7 min. (formula presented)
38. f = 0.21.