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Synlett 2007(16): 2584-2586  
DOI: 10.1055/s-2007-986650
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Novel 2,6-Diazaspiro[3.3]heptanes

Daniel Hamza*, Michael J. Stocks, Anne Décor, Garry Pairaudeau, Jeffrey P. Stonehouse
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK
Fax: +44(1509)645567; e-Mail: Daniel.Hamza@astrazeneca.com;
Further Information

Publication History

Received 22 May 2007
Publication Date:
12 September 2007 (online)

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Abstract

A practical route to 2,6-diazaspiro[3.3]heptanes is described by way of reductive amination of a readily available aldehyde with primary amines or anilines. Cyclisation proceeds in high yield and the methods reported are amenable to either library or large-scale synthesis.

Key words

aminations - combinatorial chemistry - heterocycles - ring closure - spiro compounds

4

Prolonged reaction times (>30 min) resulted in significant quantities of the des-chloro reduction product.

5

1-Benzyl-3-chloromethylazetidine-3-carbaldehyde (3): 1H NMR (400 MHz, CDCl3): δ = 9.84 (s, 1 H), 7.23-7.34 (m, 5 H), 3.95 (s, 2 H), 3.65 (s, 2 H), 3.43 (d, J = 8.2 Hz, 2 H), 3.27 (d, J = 8.2 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 200.1, 137.1, 128.4 (2 × C), 127.3, 62.7, 57.3, 49.7, 44.9. GC-MS: purity = 97.8%, base peak = 91, molecular ion = 223. HRMS: m/z [M + H]+ calcd for C12H14NOCl: 224.0842; found: 224.0849.

6

Preparation of 2-Benzyl-6-phenyl-2,6-diaza-spiro[3.3]heptane (7a): To a stirred solution of (1-benzyl-3-chloromethylazetidin-3-ylmethyl)phenylamine (0.209 g, 0.695 mmol, 1 equiv) in THF (1.5 mL) was added t-BuOK (1.53 mL, 1.53 mmol, 1.0 M solution in THF, 2.2 equiv) and the reaction was heated at 70 °C in a sealed tube. After 90 min further t-BuOK (0.7 mL, 0.7 mmol, 1.0 M solution in THF, 1 equiv) was added and heating was continued for a further 1 h. The reaction was then allowed to cool to ambient temperature, filtered to remove KCl and the solvents were evaporated. The residue was purified by column chromatography eluting with 20-100% EtOAc in isohexanes to afford 7a (209 mg, 0.487 mmol, 70%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.17-7.33 (m, 7 H), 6.73 (dt, J = 1.0, 14.6 Hz, 1 H), 6.41-6.45 (m, 2 H), 3.92 (s, 4 H), 3.58 (s, 2 H), 3.38 (s, 4 H). 13C NMR (75 MHz, CDCl3): δ = 151.6, 138.0, 128.9, 128.5, 128.4, 127.1, 117.7, 111.6, 64.5, 63.7, 62.3, 34.8. HPLC-MS: purity = 98.58%, λ = 220 nm, [M + H]+ = 265.2. HRMS: m/z [M + H]+ calcd for C18H21N2: 265.1704; found: 265.1700.

8

DMF was found to give cleaner reaction profiles than aq NMP, DMA or pyridine mixtures.

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Preparation of 2-Benzyl-6-(4-fluorobenzyl)-2,6-diaza-spiro[3.3]heptane (9a): (1-Benzyl-3-chloromethylazetidin-3-ylmethyl)(4-fluorobenzyl)amine (75 mg, 0.225 mmol) was dissolved in DMF-H2O (9:1, 3.5 mL) and heated in a sealed tube at 110 °C with stirring. After 90 min, H2O (0.4 mL) was added and the reaction was heated for a further 3 h. The reaction was allowed to cool to ambient temperature and loaded on to an SCX ion-exchange cartridge preconditioned in MeOH. After washing with MeOH the product was eluted with NH3 (1 M in MeOH) and solvents were evaporated. The residue was purified by flash column chromatography eluting with 1-30% EtOH in CH2Cl2 to afford 9a (49 mg, 0.164 mmol, 73%) as a colourless oil. 1H NMR (400 MHz, CDCl3): δ = 6.95-6.99 (m, 2 H), 7.18-7.31 (m, 7 H), 3.55 (s, 2 H), 3.50 (s, 2 H), 3.32 (s, 4 H), 3.29 (s, 4 H). 13C NMR (125 MHz, CDCl3): δ = 161.8 (d, J C-F = 244.9 Hz), 137.8, 133.6 (d, J C-F = 3.2 Hz), 129.7 (d, J C-F = 7.8 Hz), 128.24, 128.15, 126.9, 114.9 (d, J C-F = 21.2 Hz), 64.3, 64.2, 63.4, 62.6, 34.5. HPLC-MS: purity = 98.23%, λ = 220 nm, [M + H]+ = 297.2. HRMS: m/z [M + H]+ calcd for C19H22N2F: 297.1767; found: 297.1767.

12

Compound 11 was heated in a sealed tube in 20% aq DMF at 130 °C for 20 h and monitored by LC-MS.