(+/-)-[1-(2,4-Dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amine → 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(S)-methyl-ethyl]-7-chloro-3-(4-methoxy-phenyl)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

HRID 2216989Notes

Reaction equation

HRID 2216989 reaction equation
[C:1]([Si:5]([O:18][CH2:19][C@@H:20]([N:22]=[C:23]=[O:24])[CH3:21])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[N:31]=[C:30](Cl)[C:29]([CH:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH3:34])=[CH:28][N:27]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[C:1]([Si:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:18][CH2:19][C@@H:20]([N:22]1[C:28]2=[N:27][C:26]([Cl:25])=[N:31][CH:30]=[C:29]2[CH:33]([CH3:34])[N:35]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:23]1=[O:24])[CH3:21])([CH3:2])([CH3:3])[CH3:4]

Participants

5

Reactant 3

HCID 10086026(+/-)-[1-(2,4-Dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amineHCID 23665647Potassium tert-butoxideHCID 86597437(S)-tert-Butyl-2-isocyanato-propoxy-diphenylsilane

Product 1

HCID 100314941-[2-(tert-butyl-diphenyl-silanyloxy)-1-(S)-methyl-ethyl]-7-chloro-3-(4-methoxy-phenyl)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Procedure

(S)-tert-Butyl-2-isocyanato-propoxy-diphenylsilane (generated in situ from 0.440 g, 1.20 mmol, of (S)-(+)-3-(tert-butyl-diphenyl-silanyloxy)-2-methylpropionic acid) (from Example 13b supra) in hot toluene (2 mL; 120° C.) was treated with a solution of (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amine (0.35 g; 1.10 mmol) (from Example 1d supra) in toluene (2 mL). The resulting solution was kept at 120° C. for 30 minutes, then cooled to room temperature and concentrated. The residue was dissolved in anhydrous tetrahydrofuran (4 mL) and cooled in an ice-brine bath. Potassium tert-butoxide (1.0 M in tetrahydrofuran; 1.2 mL; 1.20 mmol) (Aldrich) was added dropwise and stirring continued in the cold for 15 minutes. The mixture was filtered through a bed of silica gel and eluted with ethyl acetate. Further purification with flash chromatography (Biotage 40 M; 25:75 ethyl acetate-hexanes) gave 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(S)-methyl-ethyl]-7-chloro-3-(4-methoxy-phenyl)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a mixture of diastereomers. (Yield 0.31 g; 46%). No separation of diastereomers was seen at this time.

Workup

  1. concentrationconcentrated
  2. dissolutionThe residue was dissolved in anhydrous tetrahydrofuran (4 mL)
  3. temperaturecooled in an ice-brine bath
  4. customcold for 15 minutes
  5. filtrationThe mixture was filtered through a bed of silica gel
  6. washeluted with ethyl acetate
  7. customFurther purification with flash chromatography (Biotage 40 M; 25:75 ethyl acetate-hexanes)

Sources & evidence

ORD record
ord-89cefc53cef54a238f3d087a77414b81
Source dataset
uspto-grants-2006_09
Patent number
US07112676B2

Reaction notes

Loading…