Methyl iodide → 3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-(R)-methoxy-1-(R)-methyl propoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

(R,R)-2,3 butanediol (7.78 ml, 85 mmol) was added dropwise to an ice-cold solution of sodium hydride (3.74 g, 60% dispersion in mineral oil, 93.5 mmol) in ether (800 ml), and the solution stirred at room temperature for 30 minutes. Methyl iodide (5.6 ml, 89.3 mmol) was added dropwise and the reaction stirred under reflux for 48 hours. 1,3-Dimethyl-3,4,5,6tetrahydro-2(1H)-pyrimidinone (10.24 ml, 85 mmol) was added and stirring continued for a further 90 minutes under reflux. The cooled reaction was washed with aqueous ammonium chloride solution (500 ml), dried (MgSO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of ether: pentane (10:90 to 50:50) to give a pale yellow oil. The title compound of Example 78 (100 mg, 0.2 mmol) and potassium bis(trimethylsilyl)amide (121 mg, 0.61 mmol) in the intermediate alcohol (1 ml), was heated at 110° C. for 30 hours, then the reaction cooled and concentrated under reduced pressure. The residual brown solid was purified by column chromatography on silica gel using diethylamine: ethyl acetate (5:95) as eluant, and repeated using methanol: ethyl acetate (5:95) as eluant. The product was triturated with ether to afford the title compound (7 mg, 60%) as a white solid. δ (CDCl3): 1.03 (3H, t), 1.25 (3H, d), 1.40 (3H, t), 1.48 (3H, d), 2.41 (2H, q), 2.55 (4H, m), 3.03 (2H, q), 3.15 (4H, m), 3.52 (3H, s), 3.70 (1H. m), 4.09 (3H, s), 5.39 (1H, m), 8.60 (1H, s), 8.97 (1H, s). LRMS: m/z 534 (M+1)+

1. stirringthe reaction stirred
2. temperatureunder reflux for 48 hours
3. stirringstirring
4. waitcontinued for a further 90 minutes
5. temperatureunder reflux
6. customThe cooled reaction
7. washwas washed with aqueous ammonium chloride solution (500 ml)
8. dry with materialdried (MgSO4)
9. customevaporated under reduced pressure
10. customThe residual oil was purified by column chromatography on silica gel using an elution gradient of ether: pentane (10:90 to 50:50)
11. customto give a pale yellow oil
12. temperaturethe reaction cooled
13. concentrationconcentrated under reduced pressure
14. customThe residual brown solid was purified by column chromatography on silica gel
15. customThe product was triturated with ether

ORD record

ord-6dc1de5967874eb4b728e99471aabe4c

Source dataset

uspto-grants-2001_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06251904B1