Diisopropylamine → 1h-Pyrrolo[2,3-c]pyridine-2-methanol,a-2-pyridinyl-

Temperature

-78 °C

A solution of diisopropylamine (0.43 mL, 3.07 mmol) in tetrahydrofuran (4 mL) was cooled to −78° C. under a nitrogen atmosphere. n-Butyllithium (1.24 mL of a 2.5 M solution in hexanes) was added dropwise and the reaction mixture was stirred for 30 min at −78° C. and then warmed to −30° C. A solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (Reference Example 12) (400 mg, 1.55 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.24 mL, 1.59=mmol) in tetrahydrofuran (4 mL) was added and the reaction mixture was stirred for 30 min. A solution of 2-pyridinecarboxaldehyde (0.30 mL, 3.14 mmol) in tetrahydrofuran (3 mL) was added dropwise at −30° C. The reaction mixture was allowed to warm to ambient temperature over 1.5 h. Saturated ammonium chloride solution (7 mL) was added to quench the reaction mixture. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed successively with water and brine, dried over sodium sulfate and concentrated to dryness. Purification by Biotage chromotography (silica, 2 to 18% methanol in methylene chloride) produced (pyridin-2-yl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (67 mg, 12%) as an off-white solid: mp 166-169° C.; 1H NMR (500 MHz, CD3OD) δ6.05 (1H, s), 6.39 (1H, s), 7.34-7.36 (1H, m), 7.50-7.52 (1H, m), 7.72 (1H, d, J=7.9 Hz), 7.87 (1H, d, J=6.0 Hz), 8.00 (1H, d, J=5.6 Hz), 8.52 (1H, d, J=4.8 Hz), 8.62 (1H, s); ESI MS m/z 226 [C13H11N3O+H]+; HPLC (Method A) 98.9% (AUC), tR=13.1 min.

1. temperaturewarmed to −30° C
2. stirringthe reaction mixture was stirred for 30 min
3. temperatureto warm to ambient temperature over 1.5 h
4. customto quench the reaction mixture
5. additionThe reaction mixture was diluted with water (10 mL)
6. extractionextracted with ethyl acetate (2×25 mL)
7. washThe combined organic extracts were washed successively with water and brine
8. dry with materialdried over sodium sulfate
9. concentrationconcentrated to dryness
10. customPurification by Biotage chromotography (silica, 2 to 18% methanol in methylene chloride)

ORD record

ord-2a16104e1e6346e092b42470b38421c9

Source dataset

uspto-grants-2009_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07608627B2