Triphenylphosphine → HCID 69663742, compound

Temperature

0 °C

A mixture of 4-methyl-[l,2,3]thiadiazole-5-carboxylic acid (12 mg, 0.08 mmol) in dichloromethane (2.0 mL) cooled to 0° C. was treated with triphenylphosphine (27 mg , 0.10 mmol), and N-chlorosuccinimide (14 mg, 0.10 mmol). This mixture was stirred at 0° C. for 30 min and at 25° C. for 10 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). The reaction was then stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane. The organics were washed with a saturated aqueous sodium bicarbonate solution. This solution was extracted with a 90/10 dichloromethane/methanol solution. 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 (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-methyl-[1,2,3]thiadiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (7.0 mg, 14.5%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ13.14 (broad s, 1H), 6.92–6.67 (m, 8H), 4.75 (s, 2H), 3.70 (s, 2H), 3.47 (d, J=7.32 Hz, 2H), 2.99 (s, 3H), 2.26 (s, 3H), 0.82 (m, 1H), 0.03 (m, 4H).

1. stirringThe reaction was then stirred at 25° C. for 18 h
2. washThe organics were washed with a saturated aqueous sodium bicarbonate solution
3. extractionThis solution was extracted with a 90/10 dichloromethane/methanol solution
4. dry with materialThe organics were dried over magnesium sulfate
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customThe resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min)
8. concentrationconcentrated in vacuo
9. additionThe resulting residue was diluted with dichloromethane (100 mL)
10. washwas washed with a saturated aqueous sodium bicarbonate solution (25 mL)
11. extractionThe aqueous layer was re-extracted with dichloromethane (1×50 mL)
12. dry with materialThe combined organics were dried over magnesium sulfate
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customThe resulting solid was dried in vacuo for 24 h

ORD record

ord-6f1f84c02ac145df9cbf3ed6ddbbb978

Source dataset

uspto-grants-2006_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07135475B2