Triethylamine → HCID 58739267, compound

Temperature

0 °C

A mixture of 4-acetylamino-2-methyl-thiophene-3-carboxylic acid (45 mg, 0.17 mmol) in dichloromethane (3 mL) at 25° C. was treated with triphenylphosphine (71 mg, 0.22 mmol). This mixture was cooled to 0° C. and then was treated with N-chlorosuccinimide (36 mg, 0.22 mmol). This mixture was stirred at 0° C. for 15 min and then was warmed to 25° C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (75 mg, 0.17 mmol). This solution was then cooled to 0° C. and was treated with triethylamine (38 μL, 0.22 mmol). The reaction was warmed to 25° C. and was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 4-acetylamino-2-methyl-thiophene-3-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (27.8 mg, 26.1%): EI-HRMS m/e calcd for C32H31N6O4SF (M+Na)+ 637.2004, found 637.2018.

1. temperaturewas warmed to 25° C. for 15 min
2. temperatureThis solution was then cooled to 0° C.
3. temperatureThe reaction was warmed to 25° C.
4. stirringwas stirred at 25° C. for 18 h
5. washwas washed with a saturated aqueous sodium bicarbonate solution (1×50 mL)
6. dry with materialThe organics were dried over magnesium sulfate
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. customThe resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min)
10. concentrationconcentrated in vacuo
11. additionThe resulting residue was diluted with dichloromethane (100 mL)
12. washwas washed with a saturated aqueous sodium bicarbonate solution (1×25 mL)
13. extractionThe aqueous layer was re-extracted with dichloromethane (1×50 mL)
14. dry with materialThe combined organics were dried over magnesium sulfate
15. filtrationfiltered
16. concentrationconcentrated in vacuo
17. customThe resulting solid was dried in vacuo for 24 h

ORD record

ord-99cebc67616c4c698f0c319059a828f9

Source dataset

uspto-grants-2006_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07135475B2