تفاعل #1833298

معادلة التفاعل

bendamustine hydrochloride

docosyl alcohol

dicyclohexyl carbodiimide

→

desired product

المردود 43.3%

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

المردود 43.3%

المذيبات

dichloromethane

ظروف التفاعل

المعالجة

1. 1
   أخرىSolids were removed by vacuum filtration
2. 2
   غسيلthe wetcake was washed with 50 mL
3. 3
   أخرىTwo alternate purification procedures
4. 4
   غسيلThe filtrate was washed with DI water (2×150 mL)
5. 5
   تجفيفdried over sodium sulfate
6. 6
   ترشيحfiltered
7. 7
   تركيزconcentrated to dryness in vacuo
8. 8
   أخرىThe resultant waxy residue was chromatographed on 80 g of silica gel 60, 230-400 mesh
9. 9
   غسيلeluting with a gradient
10. 10
    أخرى0.5% methanol/MDC and finally 1% methanol/MDC collecting 100-150 mL fractions
11. 11
    workup.ADDITIONFractions containing the desired product
12. 12
    تركيزconcentrated to dryness in vacuo
13. 13
    أخرىThe residue was again triturated with 20 mL of MDC
14. 14
    أخرىthe undesired solids removed by filtration
15. 15
    تركيزThe filtrate was concentrated in vacuo

الإجراء التجريبي

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).

المصدر