Concise Synthesis of 1H-Pyrazin-2-ones and 2-Aminopyrazines

Isabelle Adam; David Orain; Peter Meier

doi:10.1055/s-2004-830866

LETTER

Concise Synthesis of 1H-Pyrazin-2-ones and 2-Aminopyrazines

Isabelle Adam^a, David Orain^b, Peter Meier*^a
^a Novartis Institutes for BioMedical Research Basel, Lead Synthesis and Chemogenetics, Global Discovery Chemistry, Lichtstrasse 35, 4056 Basel, Switzerland
^b Novartis Institutes for BioMedical Research Basel, Ophthalmics, Global Discovery Chemistry, Klybeckstrasse 141, 4057 Basel, Switzerland
Fax: +41(61)3244236; e-Mail: peter.meier@pharma.novartis.com;

Abstract

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Abstract

Convenient syntheses of 1H-pyrazin-2-ones and 2-aminopyrazines are described. By coupling Boc-protected amino acids with α-amino ketones or with amino alcohols and subsequent oxidation, 1H-pyrazin-2-ones were obtained. Transformation into the corresponding pyrazine triflates and substitution with primary or secondary amines led to 2-aminopyrazines. Since these syntheses take advantage of the use of readily available starting materials (e.g., amino acids, aminoalcohols and amines) a variety of the entitled structures can be obtained in few, high yielding steps.

Key words

1H -pyrazin-2-ones - pyrazines - heterocycles - arenes - nucleophilic aromatic substitution

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References

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Typical Procedure: Preparation of 3-Ethyl-6-methyl-5-phenyl-1 H -pyrazin-2-one(3e): [1-(1-Methyl-2-oxo-2-phenyl-ethylcarbamoyl)-propyl]-carbamic acid tert-butyl ester (5a, 150 mg, 0.448 mmol) was dissolved in HCl-MeOH 1.25 N (4.48 mmol HCl) and the resulting solution was stirred 10 h at r.t. The volatiles were evaporated and pyridine (1.5 mL) was added. The resulting reaction mixture was stirred at 80 °C (opened flask!) overnight. After cooling, pyridine was removed under reduced pressure (2-4 mbar). The crude material was dissolved in CH₂Cl₂ (20 mL) and washed with brine (2 × 15 mL), dried over Na₂SO₄ and concentrated to give 3e (86 mg, 90%): ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.2 (s, 1 H), 7.47-7.79 (m, 2 H), 7.38-7.42 (m, 2 H), 7.29-7.33 (m, 1 H), 2.60-2.70 (m, 2 H), 2.23 (s, 3 H), 1.15 (t, J = 7.33 Hz, 3 H). ¹³C NMR (DMSO-d ₆): δ = 155.7, 138.2, 129.2, 128.3, 127.3, 25.6, 17.2, 11.1. HRMS (EI): m/z calcd for C₁₅H₁₇N₃O [M + H]⁺: 256.1444; found: 256.1443.

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