EFFICIENT SYNTHESIS OF A SELECTIVE Y5 RECEPTOR ANTAGONIST

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• 2-Methyl-4-pyrrolidinyl-6-[(E)-2-(3-trifluoromethylphenyl)vinyl]pyridine 8. The mixture of 3-trifluoromethylbenzylphosphonate (1.57 g, 5.3 mmol, 1.2 eq.) and aldehyde 7 (840 mg, 4.42 mmol, 1 eq.) was added dropwise to a ice-cooled solution of sodium methylate (3.43 mg, 6.37 mmol, 1.44 eq.) in dry DMF (1.53 ml) and the mixture was stirred for 9 h at room temperature. H2O (15 ml) was added and the aqueous layer was extracted with Et2O (3 × 5 ml). The organic layer was washed with a 10% citric acid solution and the combined aqueous phases were rendered alkaline with K2CO3 and then extracted with Et2O. After drying over Na2SO4, the organic layer was evaporated under reduced pressure and the obtained crude compound was purified by flash chromatography using EtOAc–MeOH: 9 : 1 with 2%(v/v) triethylamine and 340 mg of 8 were obtained. The corresponding hydrochloride was prepared by treating the free base dissolved in Et2O with gaseous hydrogen chloride. The collected solid (180 mg) was recrystallized in i-PrOH with Et2O. The global yield starting from compound 7 is 23%. M.p. 220°C (hydrochloride). Rf. 0.50 (AcOEt/MeOH 9 : 1). 1H NMR (CDCl3, 200 MHz): δ 2.08 (quint, J = 3.30 Hz, 4H), 2.55(s, 3H), 3.39 (t, J = 6.6 Hz, 4H), 6.22 (d, J = 1.9 Hz, 1H), 6.44 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 16 Hz, 1H), 7.45–7.85 (m, 5H). 13C-RMN (CDCl3, 300 MHz): δ = 157.5, 153.5, 153.12, 137.94, 130.39, 129.26, 124.52, 123.61, 105.34, 103.68, 47.30, 25.45, 24.52. Anal. calcd for C19H19F3N2. HCl. 3 H2O: C, 59.69; H, 5.67, N, 7.33. Found: C, 59.73; H, 6.10; N, 7.26.
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• 6-Methyl-4-nitropyridine-2-carbonitrile 2. A mixture of 2-methyl-4-nitropyridine N-oxide 1 (5 g; 32.5 mmol; 1 eq.) and dimethyl sulfate (3.7 ml; 39 mmol; 1.2 eq.) was stirred at 70°C for 1 h. The reaction was allowed to cool to r.t. and after filtration, the mixture was concentrated under reduced pressure. The residue was diluted with H2O (12.5 ml) and a solution of KCN (4.72 g) in H2O (25 ml) was added dropwise at −8°C. The mixture was allowed to warm to 0°C. After standing overnight, filtration and recrystallization in (i-Pr)2O gave 2.64 g of crystalline 2. Yield 50%. m.p. 76°C (lit. 76.5–77.5°C). 1H NMR (CDCl3, 200 MHz): δ 2.80 (s, 3H), 8.12 (s, 1H), 8.24 (s, 1H).
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• 6-Methyl-4-nitropyridine-2-carboxylic acid 3. A solution of 6-methyl-4-nitropyridine-2-carbonitrile 2 (2.92 g, 18 mmol, 1 eq.) in 90% H2SO4 (29.2 g) was heated for 2 h at 120°C. After cooling to room temperature, a solution of NaNO2 (3.3 g) in H2O (5.82 ml) was added and the reaction mixture was stirred for 1 h, heated at 80°C for 1 h, then poured over a mixture of H2O/ice (20 ml). The precipitate was removed by filtration and 2.96 g of 3 were obtained as yellow crystals. Yield 91%. M.p. 127°C (lit. 129°C). 1H NMR (CDCl3, 300 MHz): δ 2.83 (s, 3H), 8.18 (d, J = 1.5 Hz, 1H), 8.73 (d, J = 1.5 Hz, 1H).
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• 4-Chloro-6-methylpyridine-2-carboxylic acid 4. A solution of 6-methyl-4-nitropyridine-2-carboxylic acid 3 (2.96 g, 16.3 mmol, 1 eq.) in 37% HCl (29.6 ml) was heated at 100°C for 2 h. After evaporation under reduced pressure, the residue was diluted with H2O and the mixture was alkalinized with K2CO3 until pH = 2. The solid material was collected by filtration affording 2.2 g of compound 4. Yield 80%. m.p. 123°C (lit. 123–124°C). 1H NMR (CDCl3, 200 MHz): δ 2.63 (s, 3H), 4.51 (m, 1H), 7.45 (s, 1H), 8.04 (s, 1H).
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• N-methoxy-N,6-dimethyl-4-pyrrolidinylpyridin-2-carboxamide 5. A mixture of 4-chloro-6-methylpyridine-2-carboxylic acid 4 (2 g, 11.7 mmol, 1 eq.), pyrrolidine (1.93 ml, 23.3 mmol, 2 eq.), ammonium chloride (11.7 mmol) in n-BuOH (42 ml) was refluxed for 16 h. The solvent was removed by evaporation. The crude product 5 was dissolved in SOCl2 (60 ml) and the reaction mixture was heated at 60°C for 3 h. After cooling, SOCl2 was removed by distillation under reduced pressure giving a green oil. N-O-Dimethylhydroxylamine hydrochloride (1.2 g, 12.8 mmol, 1.1 eq.) was added dropwise to a stirred solution of the previous oil dissolved in CH2Cl2 (82 ml). The reaction mixture was then cooled to 0°C and pyridine (1.72 ml, 21.36 mmol, 2.2 eq.) was added. After stirring for 1 h, the solvent was removed by evaporation. The residue was dissolved in water (20 ml) and brine (10 ml) and extracted with EtOAc (3 × 5 ml). The organic layer dried over Na2SO4 was evaporated under reduced pressure. A yellow oil (1.5 g) of 6 was obtained after purification by flash chromatography (EtOAc–MeOH: 9 : 1 with 2% (v) triethylamine). Yield 50%. Rf. 0.23 (AcOEt/MeOH 9 : 1, TEA 2% v). 1H NMR (CDCl3, 300 MHz): δ 2.01 (quint, J = 3.35 Hz, 4H), 2.45 (s, 3H), 3.29–3.37 (m, 7H), 3.79 (s, 3H), 6.26 (d, J = 2.2 Hz, 1H), 6.56 (m, 1H).
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• 6-Methyl-4-pyrrolidinylpyridin-2-carboxaldehyde 7. Argon was passed for 20 min through a solution of 6 (1.2 g, 4.7 mmol, 1 eq.) in dry THF (47.2 ml), a solution of 1 M DiBALH in THF (14.2 ml, 14.2 mmol, 3 eq.) was added dropwise under stirring to the reaction mixture cooled until −78°C. After 2 h, a solution of 5% HCl in EtOH (14 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and the solvents were removed under reduced pressure. The residue was diluted with a saturated solution of K2CO3 and extracted with EtOAc (3 × 5 ml). The organic layer was washed with H2O (3 × 5 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a 9 : 2 (v/v) mixture of EtOAc–Heptane: 840 mg of 6 (yellow oil) were obtained. Yield 93%. Rf 0.20 (AcOEt/Heptane 9 : 2). 1H NMR (CDCl3, 200 MHz): δ 2.04 (quint, J = 3.30 Hz, 4H), 2.52 (s, 3H), 3.35 (t, J = 4.5 Hz, 4H), 6.40 (d, J = 2.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 9.95 (s, 1H).
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