Dimethylformamide → N-(1,3-Thiazol-2-yl)pyridin-2-amine 23

2-(4-Hydroxymethyl-3-methyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (10-4, 0.620 g, 2.52 mmol) was stirred in 5 mL of anhydrous dichloromethane. Anhydrous N,N-dimethylformamide (0.195 mL, 2.52 mmol) was added followed by phosphorous oxychloride (0.235 mL, 2.52 mmol). After 2 hours the reaction was quenched with half-saturated NaHCO3 (aq). The aqueous phase was extracted 3× with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford an orange-brown solid. 1H NMR indicated that this solid was composed of impure 2-(4-chloromethyl-3-methyl-pyridin-2-ylamino)thiazole-5-carbonitrile (10-5), containing BINAP dioxide impurity. This material and 4-methylcarbamoyl-piperazin-1-ium chloride (4-3, 0.445 g, 2.48 mmol) were dissolved in 3 mL DMSO. Diisopropylethylamine (0.863 mL, 4.96 mmol) was added and the reaction was stirred for 5 hours. The reaction mixture was then directly loaded onto a reverse phase purification system, which afforded titled compound, 10-6, as the TFA salt. 1H NMR (DMSO-d6) δ 11.60 (s, 1H), 9.77 (bs, 1H), 8.36 (s overlapping with d, 2H), 7.23 (d, 1H, J=5.2 Hz), 6.69 (s, 1H), 4.44 (s, 2H), 4.03 (s, 2H), 3.36 (s, 2H), 3.06 (s, 4H), 2.59 (s, 3H), 2.42 (s, 3H). MS [M+H]+=372.2. (2,6-Dichloro-pyridin-4-yl)-methanol (11-2)

1. customAfter 2 hours the reaction was quenched with half-saturated NaHCO3 (aq)
2. extractionThe aqueous phase was extracted 3× with DCM
3. dry with materialThe combined organic extracts were dried over Na2SO4
4. filtrationfiltered
5. concentrationconcentrated
6. customto afford an orange-brown solid
7. customThe reaction mixture was then directly loaded onto a reverse phase purification system, which

ORD record

ord-f24b4f5b93374a208f07ae769acf41c1

Source dataset

uspto-grants-2005_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06875767B2