Dicyclohexylcarbodiimide → 4-{5-[Bis-(chloroethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}butyric acid 5-decyl ester

HRID 1746389

Reaktionsgleichung

Reaktionsgleichung von HRID 1746389
[CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH3:25][CH2:26][CH2:27][CH2:28][CH:29](O)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.C(Cl)CCl>[CH3:25][CH2:26][CH2:27][CH2:28][CH:29]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]

Komponenten

6

Edukt 3

HCID 10868DicyclohexylcarbodiimideHCID 77082Bendamustine HydrochlorideHCID 99868Decan-5-ol

Produkt 1

HCID 901356624-{5-[Bis-(chloroethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}butyric acid 5-decyl esterAusbeute 104,7 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 142844-(Dimethylamino)pyridineKatalysatorHCID 111,2-DichloroethaneLösungsmittel

Reaktionsbedingungen

Temperatur
75 °C

Versuchsvorschrift

A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 3.0 g (7.6 mmol) of bendamustine hydrochloride, 1.21 g (7.7 mmol, 1.01 eq) of 5-decanol, 1.59 g (7.7 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 30 mL of 1,2-ethylene dichloride (EDC) and 0.1 g (0.76 mmol, 0.1 eq) of DMAP. The reaction was stirred at 75° C. for five days until an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 5 mL of EDC. The filtrate was washed with 4% aqueous sodium bicarbonate solution (1×50 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo. The residue was combined with the residue from a 10 g batch run carried out under the same conditions and the combined batches were chromatographed. The chromatography was carried out using 100 g of silica gel 60, 230-400 mesh, eluting with first 2 L of heptanes, then 1 L of 3:1 heptane/EtOAc and 1 L of 2:1 heptane/EtOAc collecting 100 mL fractions. Product containing fractions were combined and concentrated to dryness in vacuo to yield 3.97 g (7.96 mmol, 24.2%) of the product as a clear yellow oil with an HPLC purity of 99.4 A %. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=8.76 Hz, 1H), 6.93 (d, J=2.28 Hz, 1H), 6.78 (dd, J=2.40, 8.80 Hz, 1H), 4.8 (m, 1H), 3.7 (s, 8H), 3.65 (s, 3H), 2.83 (t, J=7.4 Hz, 2H), 2.44 (t, J=7.36 Hz, 2H), 2.02 (m, 2H), 1.48 (m, 4H), 1.25 (s, b, 10H), 0.84 (m, 6H).

Aufarbeitung

  1. customSolids were removed by vacuum filtration
  2. washwashed with 5 mL of EDC
  3. washThe filtrate was washed with 4% aqueous sodium bicarbonate solution (1×50 mL)
  4. dry with materialbefore drying over sodium sulfate
  5. filtrationfiltering
  6. concentrationconcentrating to dryness in vacuo
  7. customthe combined batches were chromatographed
  8. washeluting with first 2 L of heptanes
  9. additionProduct containing fractions
  10. concentrationconcentrated to dryness in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-aad9ff4ed2f242eaba27abe70c69b6e2
Quelldatensatz
uspto-grants-2015_10
Patentnummer
US09150517B2

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