Synthesis of a 4-Aryl-2-anilinopyrimidine Using a Germanium-Functionalised Non-Cross-Linked Polystyrene (NCPS) Support

Abstract

The use of a germanium-functionalised non-cross-linked polystyrene (NCPS) support to aid the preparation of a 2-anilino-4-arylpyrimidine is described. This compound is a key intermediate en route to various IKK-2 and JNK inhibitors.

Key words

non-cross-linked polystyrene (NCPS) - liquid-phase organic synthesis (LPOS) - germanium - soluble polymer - polymerization - pyrimidine - kinase - IKK - JNK

• References and Notes

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• 34 Procedure for Conversion of Germyl Copolymer 12 to 2-Anilino-4-arylpyrimidine 3: To a solution of enaminone germyl copolymer 12 (150 mg, ca. 0.12 mmol) and K₂CO₃ (104 mg, 0.75 mmol) in DMF (10 mL) was added 4-guanidinobenzoic acid methyl ester hydrochloride (13; 69 mg, 0.30 mmol). The resulting mixture was heated at 120 °C for 24 h. The solvent was removed in vacuo and the crude residue was dissolved in a minimum amount of CH₂Cl₂ and filtered through a short pad of Celite®. The filtrate was precipitated by dropwise addition into cold MeOH (3 ×) and collected by centrifugation. The resulting sticky pale yellow solid, copolymer 14 (150 mg) was dissolved in THF (15 mL) and recrystallized N-chlorosuccinimide (60 mg, 0.45 mmol) was added. The resulting solution was heated at 70 °C for 8 h. The solvent was removed in vacuo and the crude material was dissolved in minimum amount of CH₂Cl₂, the unwanted polymer precipitated by dropwise addition into cold MeOH and filtered off using a short pad of Celite^®. The filtrate was concentrated in vacuo and the resulting pale yellow solid was purified by flash chromatography (petroleum ether–EtOAc, 7:3) to give 2-anilino-4-arylpyrimidine 3 as a white solid (30 mg, 74%); mp 228–229 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.60 (br s, 1 H), 3.85 (s, 3 H), 7.14 (d, J = 5.0 Hz, 1 H), 7.43 (d, J = 7.0 Hz, 2 H), 7.73 (d, J = 7.0 Hz, 2 H), 7.98 (app t, J = 7.0 Hz, 4 H), 8.44 (d, J = 5.0 Hz, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 51.8, 109.0, 117.8, 121.8, 128.8, 129.1, 130.3, 135.2, 135.9, 145.2, 159.4, 159.7, 162.6, 166.0 ppm. IR (neat): 3320, 1700, 1532, 1434, 1316, 1177 cm^–1. MS (ES⁺): m/z = 340/342 (³⁵Cl/³⁷Cl, MH⁺). HRMS: m/z calcd for C₁₈H₁₅ClN₃O₂ [M + H]⁺: 340.0853; found: 340.0870 (Δ = 5.0 ppm).