Development of a practical synthesis of an aminoindanol-derived m1 agonist

Organic Process Research and Development

Volumn 13, Issue 2, 2009, Pages 198-208

  Hansen, Marvin M ^a   Borders, Sandra S K ^a   Clayton, Marcella T ^a   Heath, Perry C ^a   Kolis, Stanley P ^a   Larsen, Samuel D ^a   Linder, Ryan J ^a   Reutzel Edens, Susan M ^a   Smith, Justin C ^a   Tameze, Sheila L ^a   Ward, Jeffrey A ^a   Weigel, Leland O ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 65949122293     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op800243q     Document Type: Article

References (74)

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11. Preparation of resolved salt 12 was completed in the pilot plant, and the remaining steps were completed in the kilolab.
12. Sumikin is now Air Water Chemical Co., Ltd.
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40. See ref 16.
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52. (c) Initial experiments on cis-aminoindanol by Tianwei Ma were also promising.
53. Both enantiomers are available from Aldrich and several other suppliers. (1R,2R)-l-amino-2-indanol (26) was purchased on kilo scale from Arran Chemical Company.
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60. Calculated heat of decomposition = 1.22 kcal/g.
61. For a review of nitrate ester chemistry see: (a) Boschan, R.; Merrow, R. T.; van Dolah, R. W. Chem. Rev. 1955, 55, 485-510.
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68. (f) After our work was completed, ref 2b described a related nitration approach. Protection of the alcohol via the sulfate ester prevented nitrate ester formation, but these classic nitration conditions in concentrated sulfuric acid present safety issues and a scale-up challenge to control the reaction and quench exotherm. In addition, four unit operations are required to afford the freebase nitro-aminoindanol 7.
69. Purchased from Sumikin. See ref 5a for preparation.
70. 3: C, 60.33; H, 5.06; N, 7.82. Found: C, 60.11; H, 4.87; N, 7.72.
71. 2: C, 67.08; H, 4.38; N, 8.69 Found: C, 67.01; H, 4.47; N, 8.74.
72. 3: C, 61.02; H, 3.98; N, 7.91 Found: C, 61.02; H, 4.04; N, 7.82.
73. See refs 2b and 5b.
74. 5) has a noxious odor and liberates the toxic and flammable gas hydrogen sulfide on exposure to moisture. All kilo-scale reaction mixtures should be vented to an NaOCl/NaOH scrubber, and lab-scale experiments should be in a fume hood.