4-chloro-2-fluoro-7H-pyrrolo[2,3-d]pyriMidine synthesis

Yield: 53%

Reaction Conditions:

Stage #1:4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine with pyridine;tert.-butylnitrite;hydrogen fluoride at -60 - -40;Teflon bottle;
Stage #2: with potassium carbonate in chloroform;waterCooling;

Steps:

11.a
Preparation of intermediate compound (78)a. To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (74) (0.464 g, 2.75 mmol) in HF in pyridine (10 mL, 70% HF in 30% pyridine) in a Teflon bottle cooled to -60 ⁰C was added dropwise t-butyl nitrite (0.98 mL, 8.25 mmol). The reaction was allowed to warm to -40 ⁰C over a 2-h period and diluted with chloroform (100 mL). The reaction mixture was carefully poured into ice cold solution of water containing K₂CO₃ (3 g). The reaction mixture was neutralized with saturated aqueous solution OfNaHCO₃. The organic layer was separated, washed with brine (25 mL), dried, filtered and concentrated in vacuo. The residue obtained was purified by flash column chromatography (silica gel, 24 g, eluting with 0-100% ethyl acetate in hexane) to furnish 4-Chloro- 2-fluoro-7H-pyrrolo[2,3-^pyrimidine (78) (0.25 g, 53%) as an off-white solid; mp 180.0 ⁰C; ¹H NMR (300 MHz, DMSO) δ 12.72 (s, IH), 7.68 (d, J= 3.6, IH), 6.67 (d, J= 3.6, IH); ¹⁹F NMR (300 MHz, DMSO) δ -54.77. MS: Analysis: Calcd for C₆H₃ClFN₃: C, 42.01; H, 1.76; N, 24.49; Cl, 20.67; Found: C, 42.23; H, 1.70; N, 24.58; Cl, 20.40.

References:

BIOCRYST PHARMACEUTICALS, INC.;BABU, Yarlagadda, S.;CHAND, Pooran;KOTIAN, Pravin, L.;KUMAR, V., Satish WO2010/14930, 2010, A2 Location in patent:Page/Page column 57-58