Piperidine → (2R)-1-[(5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl)oxy]-3-piperidin-1-ylpropan-2-ol

HRID 339782Notes

Reaction equation

HRID 339782 reaction equation
FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.NC1[N:25]2[CH2:26][CH2:27]N=[C:24]2[C:23]2[CH:22]=CC(O)=C(OC)C=2N=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][O:39][C:40]1[C:49]2[N:48]=[C:47]([NH2:50])[N:46]3[CH2:51][CH2:52][N:53]=[C:45]3[C:44]=2[CH:43]=[CH:42][C:41]=1[O:54][CH2:55][C@H:56]1[CH2:58][O:57]1.N1CCCCC1>CN(C=O)C>[OH:57][C@H:56]([CH2:58][N:25]1[CH2:24][CH2:23][CH2:22][CH2:27][CH2:26]1)[CH2:55][O:54][C:41]1[CH:42]=[CH:43][C:44]2[C:45]3[N:46]([CH2:51][CH2:52][N:53]=3)[C:47]([NH2:50])=[N:48][C:49]=2[C:40]=1[O:39][CH3:38]

Participants

6

Reactant 4

HCID 8082PiperidineHCID 10796Cesium carbonateHCID 178493836HCID 178493836, compound2×HCID 178493879HCID 178493879, compound2×

Product 1

HCID 178493885(2R)-1-[(5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl)oxy]-3-piperidin-1-ylpropan-2-olYield 79.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a slurry of 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bis(trifluoroacetate) (Intermediate E, 3.00 g, 6.52 mmol) in DMF (72 mL) was added caesium carbonate (10.62 g, 32.6 mmol, 10.0 equiv.) and the resulting slurry was stirred at room temperature for 1.5 hr, followed by the addition of (R)-glycidyl methanesulfonate (Intermediate F, Step 1, 45 mL, 0.29 M in DMF, 13.0 mmol, 2.0 equiv.). This mixture was stirred at 60° C. for 12 hr and concentrated under reduced pressure to a volume of approximately 50 mL and divided into 3 portions. Each portion was treated with 2.15 mL piperidine (6.45 mL total, 65.2 mmol, 10 equiv.) and was heated in a microwave reactor for 45 min. at 140° C. The combined resulting mixtures were concentrated under reduced pressure. The resulting solids (1.93 g) were purified by MPLC to give N-(8-{[(2R)-2-hydroxy-3-(piperidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)amine (1.93 g, 79%): 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.30-1.43 (m, 1H), 1.56-1.70 (m, 2H), 1.70-1.84 (m, 2H), 2.88-3.04 (m, 2H), 3.11-3.32 (m, 2H), 3.42-3.52 (m, 2H), 3.82 (s, 3H), 4.09-4.17 (m, 4H), 4.28-4.38 (m, 3H), 7.24 (d, J=9.4 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H).

Workup

  1. stirringThis mixture was stirred at 60° C. for 12 hr
  2. concentrationconcentrated under reduced pressure to a volume of approximately 50 mL
  3. temperaturewas heated in a microwave reactor for 45 min. at 140° C
  4. customThe combined resulting mixtures
  5. concentrationwere concentrated under reduced pressure
  6. customThe resulting solids (1.93 g) were purified by MPLC

Sources & evidence

ORD record
ord-03914478ff6e4e6e9dea74bcd6d98c1f
Source dataset
uspto-grants-2014_11
Patent number
US08895549B2

Reaction notes

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