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Step 1: (Tetrahydro-pyran-4-yl)-acetaldehyde A 500 mL RBF under nitrogen charged with DCM (96 mL) and oxalyl chloride (3.6 mL, 42 mmol) was cooled to -60C. Dimethyl sulfoxide (6.5 mL, 92 mmol) was added dropwise and the mixture stirred 10 min. A solution of <strong>[4677-18-3]2-tetrahydropyran-4-ylethanol</strong> (5 g, 40 mmol) in DCM (40 mL) was added slowly and this mixture was stirred 15 minutes. TEA (30 mL, 200 mmol) was subsequently added slowly and the temperature allowed to rise to -30C. The cooling bath was then removed and the reaction warmed to rt. The reaction was quenched with water and the aqueous layer was extracted with DCM (3x). The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude oil was purified on silica gel to give (tetrahydro-pyran-4-yl)-acetaldehyde (3.7 g, 72%).
With pyridinium chlorochromate; In dichloromethane; at 20℃; for 5h;
To a solution of 2-(tetrahydro-pyran-4-yl)-ethanol (13 g, 0.1 mol) in dichloromethane (150 mL) was added pyridinium chlorochromate (43 g, 0.2 mol) portion-wise at room temperature. The dark suspension was stirred at room temperature for 5 h. The reaction mixture was filtered through a short pad of silica gel. The filtrate was concentrated in vacuo to afford (tetrahydro-pyran-4-yl)-acetaldehyde (6.5 g, 50%) as a yellow oil which was used in the next step without purification.
With pyridinium chlorochromate; In dichloromethane; at 16 - 19℃; for 17h;
[00107] A mixture of <strong>[4677-18-3]2-(tetrahydro-2H-pyran-4-yl)ethanol</strong> (11.70 g, 89.9 mmol) and pyridinium chlorochromate (38.8 g, 179.8 mmol) in CH2C12 (200 mL) was stirred at 16-19 C for 17 h. TLC (petroleum ether: ethyl acetate = 3: 1) showed the reaction was complete. The mixture was filtered with Kieselguhr and the filtrate (150 mL) was used for the next step directly without further purification.
With pyridinium chlorochromate; In dichloromethane; at 16 - 19℃; for 17h;
A mixture of <strong>[4677-18-3]2-(tetrahydro-2H-pyran-4-yl)ethanol</strong> (11.70 g, 89.9 mmol) and pyridinium chlorochromate (38.8 g, 179.8 mmol) in CH2C12 (200 mE) was stirred at 16-19 C.for 17 h. TEC (petroleum ether:ethyl acetate=3:1) showed the reaction was complete. The mixture was filtered with Kieselguhr and the filtrate (150 mE) was used for the next step directly without further purification.
With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In N,N-dimethyl acetamide; at 120℃;Inert atmosphere;
4-Chloro-3-aminopyridine (200 mg, 1.56 mmol) was dissolved in DMA (4 mL) and Pd2(dba)3 (71.2 mg, 0.08 mmol), X-Phos (74.2 mg, 0.16 mmol), potassium acetate (458 mg, 4.67 mmol) and (tetrahydro-pyran-4-yl)-acetaldehyde (598 mg, 4.67 mmol) were added under nitrogen. The reaction mixture was heated at 120 °C overnight, cooled to r.t. and partitioned between water (100 mL) and DCM (100 mL). The aqueous fraction was concentrated in vacuo and the residue was dissolved in DCM (100 mL), dried (MgS04) and concentrated in vacuo to give the crude title compound as an orange/brown solid (314 mg, 99.8percent). LCMS (ES+): 203.1 (M+H)+.
With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; XPhos; In N,N-dimethyl acetamide; at 120℃;Inert atmosphere;
4-Chloro-3-aminopyridine (200 mg, 1.56 mmol) was dissolved in DMA (4 mL) and Pd2(dba)3 (71.2 mg, 0.08 mmol), X-Phos (74.2 mg, 0.16 mmol), potassium acetate (458 mg, 4.67 mmol) and (tetrahydro-pyran-4-yl)-acetaldehyde (598 mg, 4.67 mmol) were added under nitrogen. The reaction mixture was heated at 120° C. overnight, cooled to r.t. and partitioned between water (100 mL) and DCM (100 mL). The aqueous fraction was concentrated in vacuo and the residue was dissolved in DCM (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as an orange/brown solid (314 mg, 99.8percent). LCMS (ES+): 203.1 (M+H)+.