Solid-Phase Synthesis of N-Alkylated Naltrindoles Using a 3-Nitrobenzyl Safety-Catch Linker

Hiroshi Ohno; Hiroshi Tanaka; Takashi Takahashi

doi:10.1055/s-2004-815414

LETTER

Solid-Phase Synthesis of N-Alkylated Naltrindoles Using a 3-Nitrobenzyl Safety-Catch Linker

Hiroshi Ohno^b, Hiroshi Tanaka^a, Takashi Takahashi*^a
^a Department of Applied Chemistry, Tokyo Institute of Technology, Meguro, Tokyo 152-8552, Japan
^b Department of Medicinal Chemistry, Pharmaceutical Research Laboratory, Toray Industries, Inc., 1111 Tebiro, Kamakura, Kanagawa 248-8555, Japan
Fax: +81(3)57342884; e-Mail: thiroshi@apc.titech.ac.jp;

Abstract

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Abstract

We describe an effective solid-phase synthesis of N-substituted naltrindoles using a nitro benzyl safety-catch linker. The linker is stable to both strongly acidic and basic conditions and is cleaved under mildly acidic conditions after conversion of the nitro group to an amide group. Using the linker, a combinatorial synthesis of N-substituted naltrindoles involving the Fischer indole synthesis and N-alkylation was accomplished to provide 16 N-substituted naltrindoles.

Key words

combinatorial chemistry - Fischer indole synthesis - linker - opioid - solid-phase synthesis

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References

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Spectra of 5aA: ¹H NMR (400 MHz, CD₃OD): δ = 0.25-0.42 (2 H, m), 0.57-0.77 (2 H, m), 1.03 (1 H, m), 1.76-1.87 (1 H, m), 2.40-3.60 (9 H, m), 2.73 (1 H, d, J = 15.6 Hz), 5.55 (1 H, d, J = 17.3 Hz), 5.60 (1 H, d, J = 17.3 Hz), 5.65 (1 H, s), 6.62 (1 H, s), 6.62 (1 H, s), 6.96-7.00 (1 H, m), 7.05-7.09 (1 H, m), 7.16-7.29 (6 H, m), 7.43 (1 H, d, J = 7.8 Hz), 8.54 (1 H, s). ESI-MS: 505 (M + H⁺).

The ratio was determined by HPLC-MS analysis of crude material using UV absorption at 254 nm.

Spectra of 5aAA: ¹H NMR (400 MHz, CD₃OD): δ = 0.33-0.48 (2 H, m), 0.66-0.85 (2 H, m), 1.11 (1 H, m), 1.72-1.87 (1 H, m), 2.55-3.57 (10 H, m), 4.59 (2 H, s), 4.51-4.67 (2 H, m), 5.66 (1 H, s), 6.66 (1 H, s), 6.66 (1 H, s), 6.96-7.12 (9 H, m), 7.21-7.26 (4 H, m), 7.38 (1 H, d, J = 7.8 Hz), 8.53 (2 H, s). ESI-MS: 595 (M + H⁺).

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