Sodium hydride → 4-{1-[5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

HRID 1887657Notes

Reaction equation

HRID 1887657 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:12]4[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].C1([O:35][C:36](=O)[NH:37][C:38]2[CH:42]=[C:41]([C:43]3([C:46](C)(C)[O:47][SiH2]C(C)(C)C)[CH2:45][CH2:44]3)[O:40][N:39]=2)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[C:23]([O:22][C:20]([N:18]1[CH2:19][C:12]2[C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([C:36](=[O:35])[NH:37][C:38]3[CH:42]=[C:41]([C:43]5([CH2:46][OH:47])[CH2:44][CH2:45]5)[O:40][N:39]=3)[CH:2]=[CH:3]4)=[N:16][CH:15]=[N:14][C:13]=2[CH2:17]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 2724141Tetrabutylammonium FluorideHCID 59394637Tert-butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylateHCID 131729884{5-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclopropyl]-isoxazol-3-yl}-carbamic acid phenyl ester

Product 1

HCID 675388064-{1-[5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of tert-butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (2 g, 5.68 mmol) in DMF (50 mL), at 0° C., NaH (0.681 g, 17.0 mmol) and {5-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclopropyl]-isoxazol-3-yl}-carbamic acid phenyl ester (3.09 g, 7.95 mmol) are added. After 1 h the reaction is complete. After quenching with water, the organics are extracted with EtOAc and the fractions combined, dried and evaporated. The crude product is dissolved in THF (10 mL) at 0° C. and TBAF (17.0 ml, 17.03 mmol) is added. After 2 h at it the reaction is complete and is quenched with NH4Cl and extracted with EtOAc. The product is separated with FCC eluting with 50:50 heptane:EtOAc to give 4-{1-[5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester which is then dissolved in DCM (10 mL) and TFA (10 mL) is added. The reaction is stirred for 20 minutes. the organics are then evaporated and the crude product is taken up in EtOAc and NH4OH (37% in water) is added to free-base the amine. Then the flask is again subjected to vacuum to remove the excess EtOAc. The crude product is then loaded onto a silica gel column and eluted with DCM:MeOH:NH4OH 100:0:0 to 90:9.5:0.5 to give the title compound. MS (ESI) m/z 433.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.25 (s, 1H) 8.65 (d, J=2.02 Hz, 1H) 8.31 (d, J=8.84 Hz, 1H) 8.18 (d, J=3.79 Hz, 1H) 7.50 (d, J=2.53 Hz, 1H) 7.18 (dd, J=9.09, 2.27 Hz, 1H) 6.80-6.82 (m, 2H) 4.99 (s, 1H) 4.58-4.67 (m, 4H) 3.66 (d, J=5.81 Hz, 2H) 1.10-1.11 (m, 2H) 1.03-1.04 (m, 2H).

Workup

  1. customAfter quenching with water
  2. extractionthe organics are extracted with EtOAc
  3. customdried
  4. customevaporated
  5. dissolutionThe crude product is dissolved in THF (10 mL) at 0° C.
  6. waitAfter 2 h at it the reaction is complete
  7. customis quenched with NH4Cl
  8. extractionextracted with EtOAc
  9. customThe product is separated with FCC
  10. washeluting with 50:50 heptane

Sources & evidence

ORD record
ord-06170e7276a84884be4d8d591698599c
Source dataset
uspto-grants-2013_08
Patent number
US08501756B2

Reaction notes

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