Water → 5-Bromopyridine-2-carboxylic acid

Temperature

80 °C

5-Bromo-2-pyridinecarbonitrile (1 g, 5.464 mmol) was dissolved in EtOH (20 mL) and water (20 mL) and treated with potassium hydroxide (1.53 g, 27.32 mmol). The reaction mixture was heated to 80° C. for 24 h. The solvent was removed under vacuum and the residue was taken up in water and acidified to pH 4 with 2M HCl. The aqueous layer was extracted with ethyl acetate (×3) and the combined organic layers dried and concentrated to give 5-bromo-2-pyridinecarboxylic acid (0.704 g) as an orange solid which was used in step 2. Step 2: The acid from step 1 (0.702 g, 3.475 mmol) was suspended in DCM (40 mL) under argon, DMF (1 drop) was added and the mixture was cooled in an ice-bath. Oxalyl chloride was added portion-wise over 5 minutes and the mixture was then heated to 40° C. for 90 minutes. On cooling, the solvent was removed to produce 5-bromo-2-pyridinecarbonyl chloride (0.801 g) as a brown solid which was used in step 3. Step 3: The acid chloride from step 2 (0.801 g, 3.633 mmol) in DCM (10 mL) was added to a solution of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.928 g, 2.906 mmol) in DCM (20 mL). Triethylamine (1.009 mL, 7.266 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was re-extracted with DCM (×2) and the combined organics were dried and concentrated to give the crude product which was purified by column chromatography. Elution with a 0-50% ethyl acetate/petroleum ether gradient yielded the title compound as a yellow oil (1.432 g). δH (CDCl3, 400 MHz) 8.34 (1H, br.s), 7.72 (1H, br.d), 7.38 (1H, br.d), 7.18 (2H, br.m), 6.98 (2H, br.s), 4.17 (1H, br.s), 3.79 (1H, d), 3.51 (3H, s), 3.46 (1H, d), 3.32 (1H, d), 3.07 (1H, td), 2.68 (1H, d), 2.47 (1H, d), 2.10 (1H, dd), 1.98 (1H, m), 1.45 (9H, s), 1.19 (3H, d). MS (ES): MH+ 503/505. Description 73

1. customThe solvent was removed under vacuum
2. extractionThe aqueous layer was extracted with ethyl acetate (×3)
3. customthe combined organic layers dried
4. concentrationconcentrated

ORD record

ord-02ad39644bee458f9b3009957abfcb5a

Source dataset

uspto-grants-2010_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07700599B2