Hydrochloric Acid → 7-(3-azetidinyl)-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

HRID 1910017Notes

Reaction equation

HRID 1910017 reaction equation
[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[CH2:15][CH2:14]4)=[CH:9][N:8]([CH:30]3[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.O1CCOCC1>CN(C=O)C.CO.C(Cl)Cl>[NH:32]1[CH2:31][CH:30]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[CH2:15][CH2:14]4)=[CH:9]2)[CH2:33]1

Participants

7

Reactant 3

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 668234481,1-dimethylethyl 3-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate

Product 1

HCID 668240497-(3-azetidinyl)-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amineYield 63.9%

Reagents, catalysts & solvents 3

HCID 887MethanolSolvent2×HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
50 °C

Procedure

To 1,1-dimethylethyl 3-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate (198 mg, 0.368 mmol) was added 4N HCl in dioxane (4 mL, 16.00 mmol). The starting material was oiling out of solution and even heating to 50 degrees C. overnight did not effect conversion. The reaction was then concentrated and DCM (4 mL) and TFA (2 ml) was added. The SM dissolved into solution and after 1 hr the reaction was complete. The reaction was concentrated then diluted with EtOAc (20 mL) and then washed with Sat. Na2CO3. A precipitate cashed out of solution and the mixture was extracted with a mixture of 20% isoproyl alcohol in DCM (3×50 ml). The organics were pooled and dried over Na2SO4, filtered and concentrated to give a yellow oil. The oil was dissolved in 1 ml of DMF and then loaded on to a 10 g Biotage column with 0 to 100% DCM in 95:5:1 mixture of DCM:MeOH:1NH4OH for 15 min then 100% 95:5:1 mixture of DCM:MeOH:1NH4OH for 15 minutes to isolate 7-(3-azetidinyl)-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (103 mg, 0.235 mmol, 63.9% yield) as a clear oil. LC-MS (ES) m/z=439.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J=8.34 Hz, 1H), 8.13 (s, 1H), 7.62 (s, 1H), 7.36 (s, 1H), 7.25-7.30 (m, 1H), 7.23 (d, J=7.33 Hz, 1H), 7.06-7.14 (m, 3H), 6.09 (br. s., 2H), 5.50 (t, J=7.45 Hz, 1H), 4.22 (t, J=8.34 Hz, 2H), 3.91-3.96 (m, 2H), 3.78-3.85 (m, 4H), 3.18-3.25 (m, 2H), 2.31 (s, 3H).

Workup

  1. customovernight
  2. concentrationThe reaction was then concentrated
  3. additionDCM (4 mL) and TFA (2 ml) was added
  4. dissolutionThe SM dissolved into solution and after 1 hr the reaction
  5. concentrationThe reaction was concentrated
  6. additionthen diluted with EtOAc (20 mL)
  7. washwashed with Sat. Na2CO3
  8. extractionthe mixture was extracted with a mixture of 20% isoproyl alcohol in DCM (3×50 ml)
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto give a yellow oil

Sources & evidence

ORD record
ord-c9b7e77f9e6e412e9c295acdaeae3fd2
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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