Citric Acid → 8-Cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one

Temperature

-40 °C

2-(Diethoxy-phosphoryl)-propionic acid ethyl ester (15.24 g, 64 mmol) was dissolved in tetrahydrofuran (100 mL) to which n-butyl lithium (47.7 mL, 119 mmol, 2.5 M in hexanes) was slowly added at −70° C. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (15 g, 63 mmol) was dissolved in tetrahydrofuran (70 mL) then added to the reaction mixture allowing the reaction to warm to −40° C. After 3 hours the reaction was warmed to room temperature, poured into cold 1 N citric acid and extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a yellow oil which was purified by silica gel chromatography. The resulting oil was dissolved to 1,8-diazabicyclo[5.4.0]undec-7-ene (75 mL) and heated to 150° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (350 mL), washed with 5% HCl and brine, dried over MgSO4, then filtered and concentrated in vacuo The remaining residue was diluted with diethyl ether and the precipitated solid was filtered off to give 8-cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (6.33 g, 31.3%). 1H NMR δ(400 MHz, CDCl3) 8.52 (s, 1H), 7.39 (d, J=1.2 Hz, 1H), 5.96, (m, 1H), 2.59 (s, 3H), 2.30 (m, 2H), 2.19 (d, J=1.2 Hz, 3H), 2.07 (m, 2H), 1.86 (m, 2H), 1.67 (m, 2H).

1. additionwas slowly added at −70° C
2. additionthen added to the reaction mixture
3. customthe reaction
4. temperatureAfter 3 hours the reaction was warmed to room temperature
5. extractionextracted with diethyl ether
6. washThe organic layer was washed with brine
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated
10. customto give a yellow oil which
11. customwas purified by silica gel chromatography
12. dissolutionThe resulting oil was dissolved to 1,8-diazabicyclo[5.4.0]undec-7-ene (75 mL)
13. temperatureheated to 150° C. for 4 hours
14. temperatureThe reaction mixture was cooled to room temperature
15. additiondiluted with ethyl acetate (350 mL)
16. washwashed with 5% HCl and brine
17. dry with materialdried over MgSO4
18. filtrationfiltered
19. concentrationconcentrated in vacuo The remaining residue
20. additionwas diluted with diethyl ether
21. filtrationthe precipitated solid was filtered off

ORD record

ord-69cf5006f8eb4b2c98cf319c430e1525

Source dataset

uspto-grants-2008_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07456168B2