تفاعل #1833303

معادلة التفاعل

DIPEA

bendamustine hydrochloride

HATU

L-alanine methyl ester hydrochloride

DIPEA

→

desired product

المردود 63.3%

(S)-2-(4-{5-[Bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzoimidazol-2-yl}-butyrylamino)-propionic acid methyl ester

المردود 63.3%

المذيبات

DMF

DMF

ظروف التفاعل

المعالجة

1. 1
   درجة الحرارةthermocouple, cooling
2. 2
   workup.ADDITIONbath, addition funnel and nitrogen in/outlet
3. 3
   workup.ADDITIONwas added over 2 minutes
4. 4
   أخرىexothermed to 9° C.
5. 5
   أخرىThe batch was quenched onto 400 mL of 1:1 ethyl acetate/DI water
6. 6
   أخرىThe layers were separated
7. 7
   غسيلthe organic was washed with 10% sodium hydrogen phosphate (1×200 mL), 8% sodium bicarbonate 91×200 mL) and brine (1×200 mL)
8. 8
   تجفيفbefore drying over sodium sulfate
9. 9
   ترشيحfiltering
10. 10
    أخرىevaporating to dryness in vacuo
11. 11
    أخرىThe residue was purified by chromatography
12. 12
    غسيلeluting with 1% MeOH/MDC (3 L), 2.5% MeOH/MDC (1 L) and 5% MeOH/MDC (500 mL)
13. 13
    أخرىcollecting ˜100 mL fractions
14. 14
    workup.ADDITIONThe product containing fractions
15. 15
    تركيزconcentrated to dryness in vacuo

الإجراء التجريبي

A 250 mL three neck round bottom flask equipped with a stir bar, thermocouple, cooling bath, addition funnel and nitrogen in/outlet was charged with 10 g (25.3 mmol) of bendamustine hydrochloride, 10.6 g (27.8 mmol) of HATU and 100 mL of DMF. The batch was cooled to 1.9° C. where 8.8 mL (6.54 g, 50.6 mmol) of DIPEA was added over 2 minutes. The reaction exothermed to 9° C. and became orange. A solution of 3.57 g (25.6 mmol) of L-alanine methyl ester hydrochloride and 6.2 mL (4.57 g, 35.4 mmol) of DIPEA in 20 mL of DMF was added drop-wise over 10 minutes at 4.9-5.7° C. The reaction was slowly warmed to RT over one hour and stirred for three hours at which time an in process assay indicated the reaction was complete. The batch was quenched onto 400 mL of 1:1 ethyl acetate/DI water. The layers were separated, the organic was washed with 10% sodium hydrogen phosphate (1×200 mL), 8% sodium bicarbonate 91×200 mL) and brine (1×200 mL), before drying over sodium sulfate, filtering and evaporating to dryness in vacuo. The residue was purified by chromatography using 100 g of silica gel 60, 230-400 mesh, eluting with 1% MeOH/MDC (3 L), 2.5% MeOH/MDC (1 L) and 5% MeOH/MDC (500 mL) collecting ˜100 mL fractions. The product containing fractions were combined and concentrated to dryness in vacuo to yield 7.1 g (16.0 mmol, 63.3%) of the desired product as a white solid with an HPLC purity of 97.4A %. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=6.92 Hz), 1H), 7.40 (d, J=8.84 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 6.86 (dd, J=2.32, 8.88 Hz), 4.25 (q, 1H), 3.72 (s, 8H), 3.71 (s, 3H), 3.62 (s, 3H), 2.87 (t, J=7.48 Hz, 2H), 2.25 (t, J=7.52 Hz, 2H), 1.99 (m, 2H), 1.26 (d, J=7.32 Hz, 3H).

المصدر