反応 #1833298

反応方程式

bendamustine hydrochloride

docosyl alcohol

dicyclohexyl carbodiimide

→

desired product

収率 43.3%

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

収率 43.3%

溶媒

dichloromethane

反応条件

後処理

1. 1
   その他Solids were removed by vacuum filtration
2. 2
   洗浄the wetcake was washed with 50 mL
3. 3
   その他Two alternate purification procedures
4. 4
   洗浄The filtrate was washed with DI water (2×150 mL)
5. 5
   乾燥dried over sodium sulfate
6. 6
   ろ過filtered
7. 7
   濃縮concentrated to dryness in vacuo
8. 8
   その他The resultant waxy residue was chromatographed on 80 g of silica gel 60, 230-400 mesh
9. 9
   洗浄eluting with a gradient
10. 10
    その他0.5% methanol/MDC and finally 1% methanol/MDC collecting 100-150 mL fractions
11. 11
    workup.ADDITIONFractions containing the desired product
12. 12
    濃縮concentrated to dryness in vacuo
13. 13
    その他The residue was again triturated with 20 mL of MDC
14. 14
    その他the undesired solids removed by filtration
15. 15
    濃縮The filtrate was concentrated in vacuo

実験手順

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).

出典