Ethyl Acetate → 5-{1-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

HRID 1910039Notes

Reaction equation

HRID 1910039 reaction equation
Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26]([CH2:30][C:31](O)=[O:32])[N:25]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(OC(=O)C)C>CN(C)C=O>[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[N:25]=1

Participants

7

Reactant 5

HCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 572875(3,5-Dimethyl-1H-pyrazol-1-yl)acetic acidHCID 668234705-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride

Product 1

HCID 534686615-{1-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amineYield 43.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a mixture of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride (175 mg, 0.517 mmol) and (3,5-dimethyl-1H-pyrazol-1-yl)acetic acid (80 mg, 0.517 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was added DIPEA (0.271 mL, 1.552 mmol) dropwise. The mixture was cooled in an ice bath, and T3P (1-propanephosphonic acid cyclic anhydride), 50% in ethylacetate (˜1.68M) (0.370 mL, 0.621 mmol) was then added dropwise. After stirring 30 minutes, the ice bath was removed and the mixture was allowed to warm to room temperature and stir 2 hours. The mixture was diluted with water (˜5 mL) and basified to pH 7-8 with 0.5M NaOH. Methanol was added to give a clear solution. This solution was loaded onto a reversed phase C18 SF25-55g Analogix cartridge and the product purified by eluting with a gradient of 30-95% methanol-water. The combined pure fractions containing the product was evaporated and azeotroped with acetonitrile and then benzene to give a solid that was triturated with acetonitrile (˜4 mL), filtered and washed with acetonitrile to afford 5-{1-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (90 mg, 41.2% yield) as a white solid after drying under vacuum. LCMS (ES) m/z=402.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (s, 1H) 8.07 (d, J=8.1 Hz, 1H) 7.34 (s, 1H) 7.20-7.29 (m, 2H) 6.08 (br. s, 2H) 5.86 (s, 1H) 5.09 (s, 2H) 4.26 (t, J=8.3 Hz, 2H) 3.74 (s, 3H) 3.27 (t, J=8.3 Hz, 2H) 2.17 (s, 3H) 2.10 (s, 3H).

Workup

  1. temperatureThe mixture was cooled in an ice bath
  2. customthe ice bath was removed
  3. stirringstir 2 hours
  4. additionThe mixture was diluted with water (˜5 mL)
  5. additionMethanol was added
  6. customto give a clear solution
  7. customthe product purified
  8. washby eluting with a gradient of 30-95% methanol-water
  9. additionThe combined pure fractions containing the product
  10. customwas evaporated
  11. customazeotroped with acetonitrile
  12. custombenzene to give a solid
  13. customthat was triturated with acetonitrile (˜4 mL)
  14. filtrationfiltered
  15. washwashed with acetonitrile

Sources & evidence

ORD record
ord-7fb60deaa31a419390f787a163f9a9e8
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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