4-BROMOPYRROLE-2-CARBOXYLIC ACID

A solution of l-(4-bromo-lH-pyrrol-2-yl)-2, 2, 2-trichloro-ethanone (4.7 mmol), prepared as described in Belanger; Tetrahedron Lett.; 1979; 2505-2508, and 1 mL of 10percent NaOH (aq) in THF (5 mL) was stirred at room temperature for Ih. The solvent was removed and the crude was partitioned between water and ethyl acetate, then 10percent HCl was added to adjust the pH to 5. The phases were separated, the aqueous layer was re-extracted with ethyl acetate, the combined organics were dried over magnesium sulphate. After evaporation, 4-bromo-lH-pyrrole-2-carboxylic acid was obtained as a solid, which was used for the next step without further purification. Yield: 64percent; LCMS (RT): 2.74 min (Method B); MS (ES+) gave m/z: 191 and 193.Compound 25 is synthesized in 2 steps from commercially available starting materials (see figure 13). 4-Bromopyrrole-2-carboxylic acid is dissolved in anhydrous DMF under argon and cooled to 0C followed by slow addition of NaH (2.5 eq.). The reaction is allowed to varm to rt. and stirred until evolution of hydrogen ceases. 2-Methylbenzyl bromide (1.0 eq.) is added dropwise and the reaction stirred at r.t. until completion as judged by TLC. To this reaction mixtures is added Et3N (5 eq.) and HATU (1.05 eq.) followed 1-phenylpiperazine (1.05 eq.) at r.t. The reaction is stirred for 15 min. and worked up by addition of EtOAc and sat. aq . NaHCC>3. The phases are separated and the organic phase washed with sat. aq . NaHCC>3 (3x), sat. aq. NaCI (lx), dried over Na2S04and evaporated to dryness to afford crude 13.3. The crude product was purified by silica gel chromatography to afford 13.3. 13.3 was dissolved in a mixture of dioxane: H20 and degassed with argon under ultrasound. To the degassed mixture is added K2CO3 (5 eq.), 4-pyridinylboronic acid (1.5 eq.), Pd(OAc)2 (0.05 eq.) and PPti3 (0.25 eq.) under argon and the reaction mixture is heated at 80 C until completion. EtOAc and sat. aq. NaHC03 is added and the phases separated and the organic phase washed with sat. aq. NaHC03 (3x), sat. aq. NaCI (lx), dried over Na2S04and evaporated to dryness to afford crude 25. The crude product is purified by silica gel chromatography to afford pure 25.To a solution of commercially available 4-bromo-lH- pyrrole-2-carboxylic acid (1.00 g, 5.26 mmol) and Intermediate 1 (1.46 g, 5.26 mmol) in DMF (26.3 mL) were added EDC (2.02 g, 10.5 mmol), HOBT (1.61 g, 10.5 mmol) and DIPEA (2.02 mL, 11.6 mmol). After stirring at at room temperature for 1.5 h, the reaction was diluted with water and extracted with EtOAc (3x). The combined organic phases were washed with sat. NH4CI, water, brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, 100:0 to 0: 100) to yield Int-23A (1.99 g, 91%) as a white gummy solid. NMR (500MHz, CDCh) 5 9.35 (br. s., 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.10 - 7.01 (m, 2H), 6.94 - 6.87 (m, 2H), 6.67 (dd, J = 2.6, 1.5 Hz, 1H), 5.46 (dt, J = 8.5, 5.4 Hz, 1H), 4.18 - 4.06 (m, 2H), 3.87 (s, 3H), 2.99 - 2.79 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H). HPLC retention time (Method 2): 2.368 mia ; LCMS (ES): m/z 413.1 , 415.1 [M+H]+.

Molecular Weight:189.99
XLogP3:1.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:188.94254
Monoisotopic Mass:188.94254
Topological Polar Surface Area:53.1
Heavy Atom Count:9
Complexity:128
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes