High-yielding syntheses of 1-piperidin-4-yl butyro- and valerolactams through a tandem reductive animation-lactamization (reductive lactamization)

Organic Process Research and Development

Volumn 11, Issue 3, 2007, Pages 482-486

  Mapes, Christopher M ^a   Mani, Neelakandha S ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 39049126196     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op700016b     Document Type: Article

References (21)

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10. Recent literature details the direct and selective substitution of secondary amines in the presence of primary amines: Laduron, F.; Tamborowski, V.; Moens, L.; Horvath, A.; De Smaele, D.; Leurs, S. Org. Process Res. Dev. 2005, 9, 102.
11. A search using the Scifinder database was able to locate 4-(Boc-amino)-piperidine priced at $6.6/g (250 g) and 1-benzyl-4-piperidone priced at $0.31/g (5 kg).
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18. The reductive lactamization, when using sodium borohydride in methanol, required 60 h at 45 °C to yield 70% product. The mass balance was the trans-esterified, uncyclized, reductive amination product.
19. This protocol was developed after an initial iteration presented a process hazard on 10.0-g scale. When a vessel was charged with all of the reagents and heated to 60 °C directly, a severe exotherm coupled with violent off gassing was observed.
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