Ammonia → 5-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid [5-(1-aminomethyl-cyclopropyl)-isoxazol-3-yl]-amide

HRID 450312Notes

Reaction equation

HRID 450312 reaction equation
C(OC([N:8]1[CH2:16][C:15]2[C:14]([O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([C:27](=[O:39])[NH:28][C:29]3[CH:33]=[C:32]([C:34]5([CH2:37]O)[CH2:36][CH2:35]5)[O:31][N:30]=3)[CH:22]=[CH:21]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C([N:42](CC)CC)C.N.CO.C(O)(C(F)(F)F)=O>C1COCC1.CN(C1C=CN=CC=1)C>[NH2:42][CH2:37][C:34]1([C:32]2[O:31][N:30]=[C:29]([NH:28][C:27]([N:23]3[C:24]4[C:20](=[CH:19][C:18]([O:17][C:14]5[C:15]6[CH2:16][NH:8][CH2:9][C:10]=6[N:11]=[CH:12][N:13]=5)=[CH:26][CH:25]=4)[CH:21]=[CH:22]3)=[O:39])[CH:33]=2)[CH2:36][CH2:35]1

Participants

8

Reactant 5

HCID 222AmmoniaHCID 887MethanolHCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 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

Product 1

HCID 593947675-(6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid [5-(1-aminomethyl-cyclopropyl)-isoxazol-3-yl]-amide

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 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 (500 mg, 0.939 mmol) in THF (10 mL), at 0° C., triethylamine (0.262 mL, 1.88 mmol) methanesulfonyl chloride (0.110 mL, 1.41 mmol) and DMAP (11.5 mg, 0.094 mmol) are added. After 2 h the reaction is complete and is quenched with water and the organics extracted with EtOAc. The crude product following concentrationis then dissolved in THF (30 mL), and NH3 in MeOH (1.82 mL, 12.8 mmol) is added. The reaction is stirred for 36 h. At this point the volatiles are removed and the crude product is dissolved in DCM (10 mL) and then TFA (10 mL, 130 mmol) is added. After 10 minutes the volatiles are removed in vacuo. The product is dissolved in EtOAc and then NH4OH is added. The organics are removed and the crude product separated via FCC eluting with DCM:MeOH:NH4OH (100:0:0 to 92:7:1) to give the title compound. MS (ESI) m/z 432.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 1H) 8.35 (d, J=8.84 Hz, 1H) 8.15 (d, J=3.54 Hz, 1H) 7.44 (d, J=2.53 Hz, 1H) 7.11 (dd, J=9.09, 2.53 Hz, 1H) 6.77 (s, 1H) 6.70 (d, J=4.04 Hz, 1H) 4.09 (d, J=11.87 Hz, 4H) 2.94 (s, 2H) 1.05 (d, J=3.03 Hz, 4H).

Workup

  1. customis quenched with water
  2. extractionthe organics extracted with EtOAc
  3. concentrationconcentrationis
  4. dissolutionthen dissolved in THF (30 mL)
  5. customAt this point the volatiles are removed
  6. dissolutionthe crude product is dissolved in DCM (10 mL)
  7. customAfter 10 minutes the volatiles are removed in vacuo
  8. dissolutionThe product is dissolved in EtOAc
  9. additionNH4OH is added
  10. customThe organics are removed
  11. customthe crude product separated via FCC
  12. washeluting with DCM:MeOH:NH4OH (100:0:0 to 92:7:1)

Sources & evidence

ORD record
ord-872a9802afdc43029c8dc58e03a9056f
Source dataset
uspto-grants-2013_07
Patent number
US08486954B2

Reaction notes

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