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

HRID 1746116

반응식

HRID 1746116 반응식
[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.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:46]([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)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]

참가 물질

5

반응물 3

HCID 10868DicyclohexylcarbodiimideHCID 12620Behenyl AlcoholHCID 77082Bendamustine Hydrochloride

생성물 1

HCID 901357854-{5-[Bis-(chloroethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}butyric acid docosyl ester수율 43.3%

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

A 250 mL three necked round bottom flask equipped with a stir bar, thermocouple and nitrogen in/outlet was charged with 5.0 g (12.7 mmol) of bendamustine hydrochloride, 4.2 g (12.9 mmol, 1.01 eq) of docosyl alcohol, 2.7 g (12.9 mmol, 1.01 eq) of dicyclohexyl carbodiimide (DCC), 50 mL of dichloromethane (MDC) and 0.16 g (1.27 mmol, 0.1 eq) of N,N-dimethylamino pyridine (DMAP). The reaction mixture was stirred at room temperature overnight at which time an HPLC analysis indicated the reaction was complete. Solids were removed by vacuum filtration and the wetcake was washed with 50 mL. Two alternate purification procedures were developed. The filtrate was washed with DI water (2×150 mL), dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The resultant waxy residue was chromatographed on 80 g of silica gel 60, 230-400 mesh eluting with a gradient beginning with 100% MDC, then 0.5% methanol/MDC and finally 1% methanol/MDC collecting 100-150 mL fractions. Fractions containing the desired product were combined and concentrated to dryness in vacuo. The residue was again triturated with 20 mL of MDC and the undesired solids removed by filtration. The filtrate was concentrated in vacuo to yield 3.65 g (5.5 mmol, 43.1%) of the desired product as a waxy white solid with a purity of 95.7A %. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.72 Hz, 1H), 7.08 (d, J=2.28 Hz, 1H), 6.78 (dd, J=2.36, 8.72 Hz, 1H), 4.05 (t, J=6.76 Hz, 2H), 3.72 (m, 4H), 3.70 (s, 3H), 3.63 (m, 4H), 2.91 (t, J=7.44 Hz, 2H), 2.49 (t, J=7.08 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 38H), 0.88 (t, J=6.64 Hz, 3H).

후처리

  1. customSolids were removed by vacuum filtration
  2. washthe wetcake was washed with 50 mL
  3. customTwo alternate purification procedures
  4. washThe filtrate was washed with DI water (2×150 mL)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated to dryness in vacuo
  8. customThe resultant waxy residue was chromatographed on 80 g of silica gel 60, 230-400 mesh
  9. washeluting with a gradient
  10. custom0.5% methanol/MDC and finally 1% methanol/MDC collecting 100-150 mL fractions
  11. additionFractions containing the desired product
  12. concentrationconcentrated to dryness in vacuo
  13. customThe residue was again triturated with 20 mL of MDC
  14. customthe undesired solids removed by filtration
  15. concentrationThe filtrate was concentrated in vacuo

출처 및 근거

ORD 기록
ord-be7e62b48e8846fbb81910e6431ef3a9
출처 데이터셋
uspto-grants-2015_10
특허 번호
US09149464B2

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