Synlett 2015; 26(13): 1815-1818
DOI: 10.1055/s-0034-1378722
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Orthogonally Protected 2,6-Diazaspiro[3.5]nonane and 2,6-Diazaspiro[3.4]octane Analogues as Versatile Building Blocks in Medicinal Chemistry

David Orain
a  Novartis Pharma AG, Werk Klybeck, Postfach, 4002 Basel, Switzerland
,
Samuel Hintermann
a  Novartis Pharma AG, Werk Klybeck, Postfach, 4002 Basel, Switzerland
,
Maciej Pudelko*
b  Selvita S.A., Park Life Science, Bobrzynskiego 14, 30-348 Cracow, Poland   Email: maciej.pudelko@selvita.com
,
Diego Carballa
b  Selvita S.A., Park Life Science, Bobrzynskiego 14, 30-348 Cracow, Poland   Email: maciej.pudelko@selvita.com
,
Anna Jedrzejczak
b  Selvita S.A., Park Life Science, Bobrzynskiego 14, 30-348 Cracow, Poland   Email: maciej.pudelko@selvita.com
› Author Affiliations
Further Information

Publication History

Received: 25 March 2015

Accepted after revision: 07 May 2015

Publication Date:
25 June 2015 (online)


Abstract

A novel and efficient synthesis of orthogonally protected spirocyclic amines is described for the first time.

Supporting Information

 
  • References and Notes

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  • 15 Typical Procedure for Nosyl Group Removal Cs2CO3 (22.64 g, 0.069 mol) and thiophenol (5.21 mL, 0.051 mol) were successively added to a solution of nosyl-protected spiro amine 10 (18.6 g, 0.046 mol) in MeCN (150 mL). The mixture was stirred at r.t. for 16 h. After this time the starting material was consumed as judged by TLC. The reaction mixture was filtered through a short layer of Celite. The cake was washed first with EtOAc (300 mL) and further with CH2Cl2–MeOH–NH3 (7 M in MeOH, 80:18:2, 3 × 100 mL), and the collected organic layer was concentrated to give in total 31.3 g of the crude oil, which was absorbed on the minimum of silica gel and poured into a chromatography column containing a 1 cm layer of silica gel. The elution was carried out with EtOAc to wash off unpolar impurities and then with the system CH2Cl2–MeOH–NH3 (7 M in MeOH, 80:18:2) to give the product 11 (8.8 g, 89% yield) as yellow oil. LCMS (214 nm): t R = 7.8 min (89.1% content), [M + H]+ = 217.0. TLC analysis: Rf = 0.07 in CH2Cl2–MeOH–NH3 (7 M in MeOH). 1H NMR (400 MHz, CD3OD): δ = 7.36–7.19 (m, 5 H), 3.51 (s, 2 H), 3.38–3.33 (m, 4 H), 2.53–2.28 (m, 4 H), 1.65 (s, 2 H), 1.60–1.51 (m, 2 H). 13C NMR (101 MHz, CD3OD): δ = 137.93, 128.91, 127.92, 126.84, 62.73, 61.32, 55.05, 53.12, 38.27, 33.82, 21.78.
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  • 17 Intermediate 18 was also obtained from the dimesyl analogue of 17; however, the isolated yield was lower (51%).
  • 18 The p-toluenesulfonamide derivative of intermediate 18 was obtained, and the deprotection to spirocyclic amine 19 was carried out with Red-Al® in toluene under reflux; however, the isolated yield of was lower.