تفاعل #57453

معادلة التفاعل

N1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

N-hydroxybenzotriazole

(2S)-4-amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanoic acid hydrochloride

N,N-diisopropylethylamine

→

(2S)-N1-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)-2-[(2-quinolinylcarbonyl)amino]butanediamide

المردود 41.4%

المذيبات

dimethylformamide

ظروف التفاعل

المعالجة

1. 1
   أخرىThe reaction solvent was removed in vacuo
2. 2
   workup.DISSOLUTIONthe residue was dissolved in ethyl acetate
3. 3
   أخرىThe solution was transferred to a separatory funnel
4. 4
   غسيلwashed twice with 1N sodium hydrogen sulfate
5. 5
   استخلاصThe combined aqueous layers were extracted with ethyl acetate
6. 6
   غسيلThe combined organic layers were washed with 5% aqueous potassium carbonate and brine
7. 7
   تجفيفdried over anhydrous magnesium sulfate
8. 8
   ترشيحfiltered
9. 9
   أخرىevaporated in vacuo
10. 10
    أخرىThe residue was purified on a preparative TLC plate (20×20 cm, 1000 μM)
11. 11
    غسيلeluting with 97:3 chloroform
12. 12
    أخرىThe product band was removed
13. 13
    غسيلeluted with 3:1 methylene chloride
14. 14
    ترشيحmethanol, filtered
15. 15
    أخرىevaporated in vacuo
16. 16
    أخرىThe residue was triturated with hexane and diethyl ether
17. 17
    أخرىThe slurry was evaporated in vacuo to a residue
18. 18
    أخرىdried under high vacuum

الإجراء التجريبي

A mixture of N1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide (Step 1, Example 48), (73 mg, 0.168), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg, 0.18 mmol), N-hydroxybenzotriazole (24 mg, 0.18 mmol), and (2S)-4-amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanoic acid hydrochloride (57 mg, 0.18 mmol, Eur. Pat. Appl. EP 432694) was combined under an Argon atmosphere at ambient temperature in anhydrous dimethylformamide (2 mL). After addition of N,N-diisopropylethylamine (896 μL, 0.513 mmol), the mixture was stirred for 16 hours. The reaction solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was transferred to a separatory funnel and washed twice with 1N sodium hydrogen sulfate. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with 5% aqueous potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 1000 μM) eluting with 97:3 chloroform:methanol. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with hexane and diethyl ether. The slurry was evaporated in vacuo to a residue and dried under high vacuum to provide (2S)-N1-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)-2-[(2-quinolinylcarbonyl)amino]butanediamide (49 mg, 41%) as a white solid. H1-NMR (chloroform-D3): 1.52 (m, 4H), 1.75 (m, 4H), 2.82 (m, 5H), 3.10 (m, 1H), 3.82 (b, 1H), 3.84 (s, 3H), 3.91 m, 1H), 4.29 (m, 1H), 4.78 (m, 1H), 4.95 (m, 1H), 5.76 (b, 1H), 6.22 (b, 1H), 7.00 (m, 5H), 7.12 (d, 2H), 7.22 (d, 1H), 7.60 (m, 1H), 7.75 (m, 3H), 7.83 (d, 1H), 8.14 (m, 2H), 8.25 (d, 1H), 9.15 (d, 1H). MS(ESI): 704 (M+H).

المصدر