Hydrochloric Acid → HCID 178441168, compound

HRID 45097

Reaction equation

HRID 45097 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][C:6](OC3C4C(C)N(C(OC(C)(C)C)=O)CC=4N=CN=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1([C:33]([N:35]2[CH:39]=[CH:38]N=C2)=[O:34])C=CN=C1.[C:40]([C:44]1[NH:48][N:47]=C(N)C=1)([CH3:43])([CH3:42])[CH3:41].Cl.C(O)(C(F)(F)F)=O>CN(C=O)C.O.C(Cl)Cl.CCOC(C)=O>[C:40]([C:44]1[CH:38]=[C:39]([NH:35][C:33]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:34])[NH:47][N:48]=1)([CH3:43])([CH3:42])[CH3:41]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 682631,1'-CarbonyldiimidazoleHCID 5227873-Amino-5-tert-butylpyrazoleHCID 59394355tert-butyl 4-(1H-indol-5-yloxy)-5-methyl-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate

Product 1

HCID 178441168HCID 178441168, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of tert-butyl 4-(1H-indol-5-yloxy)-5-methyl-5H-pyrrolo[3,4-d]pyrimidine-6(7 H)-carboxylate (150 mg, 0.409 mmol) in DMF (4 mL) at rt, di(1H-imidazol-1-yl)methanone (86 mg, 0.532 mmol) is added followed by TEA (0.34 mL, 2.46 mmol). After 3 h at room temperature 5-tert-butyl-1H-pyrazol-3-amine (342 mg, 2.46 mmol) is added and the reaction left stirring at rt for 48 h. At this point as 1N HCl solution in water (2 mL) is added and EtOAc (5 mL) is added. The layers are separated and the water layer extracted 3 times with EtOAc. The organics are dried and evaporated. DCM (4 mL) and TFA (10 mL, 130 mmol) are added at 0° C. and the reaction allowed to warm to rt over 1 h. At this point the reaction is complete. TFA/DCM is evaporated and then the product is taken up in EtOAc (100 mL). NH4OH (20 mL) is added and then water. The organics are separated and the water layer extracted with EtOAc (2 times). The organics are dried and evaporated. The crude product is added to a silica gel column (ISCO) and eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1) to isolate 5-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-tert-butyl-2H-pyrazol-3-yl)-amide. MS (ESI) m/z 432.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50 (s, 1 H)8.33 (d, J=9.09 Hz, 1 H)7.89 (d, J=3.54 Hz, 1 H)7.41 (d, J=2.27 Hz, 1 H)7.10 (dd, J=8.97, 2.40 Hz, 1 H)6.71 (d, J=3.54 Hz, 1 H)6.37 (s, 1 H)4.71 (d, J=6.57 Hz, 1 H)4.10-4.22 (m, 2 H)1.60 (d, J=6.82 Hz, 3 H)1.37 (s, 9 H).

Workup

  1. waitthe reaction left
  2. customThe layers are separated
  3. extractionthe water layer extracted 3 times with EtOAc
  4. customThe organics are dried
  5. customevaporated
  6. temperatureto warm to rt over 1 h
  7. customTFA/DCM is evaporated
  8. additionNH4OH (20 mL) is added
  9. customThe organics are separated
  10. extractionthe water layer extracted with EtOAc (2 times)
  11. customThe organics are dried
  12. customevaporated
  13. additionThe crude product is added to a silica gel column (ISCO)
  14. washeluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1)

Sources & evidence

ORD record
ord-db7f9a207b4d45179b36ca11195173ef
Source dataset
uspto-grants-2013_09
Patent number
US08541432B2

Linked notes

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