Dimethyl Sulfoxide → [(S)-1-(2-Amino-9-fluoro-5-methyl-1,3-dioxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazolin-8-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

HRID 10335Notes

Reaction equation

HRID 10335 reaction equation
N[C:2]1([CH3:19])[N:13]2[C:14]3[C:9]([C:10](=[O:16])[NH:11][C:12]2=[O:15])=[CH:8][C:7]([F:17])=[C:6](F)[C:5]=3[CH2:4][CH2:3]1.[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C([N:35](CC)CC)C.CS(C)=O>O>[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][N:29]([C:6]2[C:5]3[CH2:4][CH2:3][CH:2]([CH3:19])[N:13]4[C:14]=3[C:9]([C:10](=[O:16])[N:11]([NH2:35])[C:12]4=[O:15])=[CH:8][C:7]=2[F:17])[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 8471TriethylamineHCID 1514396(3S)-(-)-3-(tert-Butoxycarbonylamino)pyrrolidineHCID 219792245-amino-8,9-difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione

Product 1

HCID 58681896[(S)-1-(2-Amino-9-fluoro-5-methyl-1,3-dioxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinazolin-8-yl)pyrrolidin-3-yl]carbamic acid tert-butyl esterYield 71.8%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A solution of 0.12 g (0.45 mmol) of 5-amino-8,9-difluoro-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinazoline-1,3-dione (Example 24i), 0.34 g (1.8 mmol) of (S)-3-pyrrolidinylcarbamic acid tert-butyl ester (J. Med. Chem., 1992; 35:1764), 0.2 g (2.0 mmol) of triethylamine and 7 mL of dimethyl sulfoxide is heated at 110° C. for 18 hours. The reaction is cooled to room temperature, diluted with 80 mL of ice and water and stirred at 5° C. for 1 hour. The resulting precipitate is removed by filtration, washed with water and dried in vacuo. The solid is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane/ethanol (9:1) to give 0.14 g of the title compound, mp 98–100° C.

Workup

  1. customThe resulting precipitate is removed by filtration
  2. washwashed with water
  3. customdried in vacuo
  4. customThe solid is chromatographed over flash grade silica gel (230–400 mesh)
  5. washeluting with dichloromethane/ethanol (9:1)

Sources & evidence

ORD record
ord-7529c8caf4b748479316487eac532aa3
Source dataset
uspto-grants-2006_08
Patent number
US07094780B1

Reaction notes

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