Dimethylmalonic acid → 2,2-Dimethyl-N-[3-(1-trityl-1H-imidazol-4-yl)-propyl]-malonamic acid

HRID 2408307

Reaction equation

HRID 2408307 reaction equation
C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:22][C:23]([CH3:30])([C:27](O)=[O:28])[C:24]([OH:26])=[O:25].CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[C:59]([N:78]1[CH:82]=[C:81]([CH2:83][CH2:84][CH2:85][NH2:86])[N:80]=[CH:79]1)([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl.CN(C=O)C.C(Cl)Cl.CN(C=O)C>[CH3:22][C:23]([CH3:30])([C:27]([NH:86][CH2:85][CH2:84][CH2:83][C:81]1[N:80]=[CH:79][N:78]([C:59]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:82]=1)=[O:28])[C:24]([OH:26])=[O:25]

Participants

10

Reactant 6

HCID 11686Dimethylmalonic acidHCID 12734DiisopropylcarbodiimideHCID 81531Diisopropylethylamine2×HCID 945242-Chlorotrityl chlorideHCID 181649HOAtHCID 153458253-(1-trityl-1H-imidazol-4-yl)propan-1-amine

Product 1

HCID 583390552,2-Dimethyl-N-[3-(1-trityl-1H-imidazol-4-yl)-propyl]-malonamic acid

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent2×HCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

2-Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:DMF 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in DMF for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and DMF (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtered and 3-(1-Trityl-1H-imidazol-4-yl)-propyl amine (1.8 eq; 5.40 mmol; 1.84 g), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and DMF (10 mL) was added. The resin was shaken for 2 days. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs. The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) and the combined filtrates were collected and concentrated in vacuo to yield the title compound.

Workup

  1. filtrationfiltered
  2. additionadded to the resin
  3. filtrationThe resin was filtered
  4. washwashed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each)
  5. waitThe resin was swelled in DMF for 20 mins
  6. filtrationfiltered
  7. stirringthe resin was shaken for 90 min at RT
  8. filtrationThe resin was filtered
  9. stirringThe resin was shaken for 2 days
  10. filtrationThe resin was filtered
  11. washwashed with NMP (5×20 mL) and DCM (10×20 mL)
  12. addition2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it
  13. waitwas shaked for 2 hrs
  14. washThe resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL)
  15. customthe combined filtrates were collected
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-3306912c49294a66b56590c7f04378e8
Source dataset
uspto-grants-2014_08
Patent number
US08815802B2

Linked notes

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