1-Hydroxybenzotriazole → HCID 44133332, compound

7-(2-Fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (90 mg, 0.23 mmol), O—(((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (35 mg, 0.23 mmol), HOBt (35 mg, 0.26 mmol), EDCI hydrochloride (50 mg, 0.26 mmol) and DIPEA (40 μL, 0.23 mmol) were dissolved in DMF (3 mL). The reaction was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was dissolved in hydrochloric acid in dioxane (2 mL, 4M) and stirred at RT for 10 minutes. The reaction mixture was concentrated in vacuo and the resultant residue subjected to reverse phase HPLC (gradient 20-80% acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The product was dissolved in ethyl acetate (5 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound as a yellow solid (22 mg, 20%). NMR (d6-DMSO, 400 MHz) 11.39 (1H, s), 8.68 (1H, s), 7.99 (1H, s), 7.49 (1H, dd, J=10.9, 1.8 Hz), 7.41 (2H, s), 7.14-7.17 (1H, m), 6.74 (1H, s), 5.92 (1H, t, J=8.9 Hz), 4.80-4.81 (1H, m), 4.53 (1H, s), 3.80 (1H, dd, J=9.6, 3.6 Hz), 3.56-3.66 (2H, m). LCMS (Method A): RT=7.57 min, M+H+=487.

1. concentrationthen concentrated in vacuo
2. dissolutionThe resultant residue was dissolved in ethyl acetate (10 mL)
3. washwashed with aqueous saturated sodium bicarbonate solution (10 mL)
4. extractionthe aqueous fraction extracted twice with ethyl acetate (2×10 mL)
5. washThe combined organic fractions were washed with brine
6. dry with materialdried (MgSO4)
7. concentrationconcentrated in vacuo
8. dissolutionThe resultant residue was dissolved in hydrochloric acid in dioxane (2 mL, 4M)
9. stirringstirred at RT for 10 minutes
10. concentrationThe reaction mixture was concentrated in vacuo
11. dissolutionThe product was dissolved in ethyl acetate (5 mL)
12. washwashed with aqueous saturated sodium bicarbonate solution (10 mL)
13. extractionthe aqueous fraction extracted twice with ethyl acetate (2×10 mL)
14. washThe combined organic fractions were washed with brine
15. dry with materialdried (MgSO4)
16. concentrationconcentrated in vacuo

ORD record

ord-241bd5a3d40540c99942844cd368f107

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08486963B2