Trifluoroacetic acid → racemic 5-(5-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

HRID 45096Notes

Reaction equation

HRID 45096 reaction equation
C(OC([N:8]1[CH:16]([CH3:17])[C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:40])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH:16]([CH3:17])[NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:40])[CH:35]=[CH:34][CH:33]=1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 593944775-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

Product 1

HCID 59394515racemic 5-(5-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 5-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester in DCM (20 mL), TFA (20 ml, 134 mmol) is added at 0° C. After 30 min the reaction is warmed to rt. At this point, the reaction is evaporated and the crude product is dissolved in EtOAc. A Few drops of NH4OH are added to freebase the amine and the whole mixture is then evaporated. The crude product is added to a silica gel column and is eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1) to give racemic 5-(5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 454.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50 (s, 1 H)8.33 (s, 1 H)8.06 (s, 1 H)7.94 (br. S., 2 H)7.57 (s, 1 H)7.42 (br. S., 2 H)7.12 (d, J=9.09 Hz, 1 H)6.75 (d, J=3.03 Hz, 1 H)4.70 (br. S., 1 H)4.10-4.22 (m, 2 H)1.60 (d, J=6.57 Hz, 3 H). Racemate is then separated using chiral HPLC (IA column; 40% heptane, 60% Ethanol) to give the corresponding enantiomers D-1 and D-2.

Workup

  1. customAt this point, the reaction is evaporated
  2. dissolutionthe crude product is dissolved in EtOAc
  3. additionA Few drops of NH4OH are added
  4. customthe whole mixture is then evaporated
  5. additionThe crude product is added to a silica gel column
  6. washis eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1)

Sources & evidence

ORD record
ord-ec8244377da1419a815f3ae0664b908b
Source dataset
uspto-grants-2013_09
Patent number
US08541432B2

Reaction notes

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