反应 #6783

反应方程式

triethylamine

HOAt

EDC

[2-({[((2S)-1-{(2R)-2-[(tert-butoxycarbonyl) amino]-2-cyclohexylethanoyl} pyrrolidin-2-yl)carbonyl]amino} methyl)-4-chlorophenoxy]acetic acid

glycine tertbutyl ester hydrochloride

triethylamine

HOAt

EDC

→

(6R,20aS)-16-chloro-6-cyclohexyl-2,3,6,7,9,10,18,19-octahydro-1H-pyrrolo[1,2-j][1,4,7,10,13] benzoxatetraazacyclohexadecine-5,8,11,20 (12H,20aH)-tetrone

溶剂

EtOAc

DMF

反应条件

后处理

1. 1
   洗涤washed with 50 mL each of 10% aqueous KHSO4, dilute brine, and brine
2. 2
   干燥dried over Na2SO4
3. 3
   过滤filtered
4. 4
   浓缩concentrated
5. 5
   workup.DISSOLUTIONThe residue was dissolved in 3 mL CH2Cl2
6. 6
   workup.ADDITIONwas added
7. 7
   温度then warmed to room temperature for 2 hours
8. 8
   workup.ADDITIONTo this was added 50 mL toluene
9. 9
   浓缩the mixture concentrated
10. 10
    workup.DISSOLUTIONredissolved in CH2Cl2
11. 11
    浓缩toluene and concentrated
12. 12
    workup.DISSOLUTIONThe residue was dissolved in 50 mL DMF
13. 13
    浓缩After 64 hours the reaction mixture was concentrated
14. 14
    workup.ADDITIONthe residue diluted with 50 mL EtOAc
15. 15
    洗涤washed with 20 mL each of 10% aqueous KHSO4, dilute brine, and brine
16. 16
    干燥dried over Na2SO4
17. 17
    过滤filtered
18. 18
    浓缩concentrated
19. 19
    其他Purification by flash chromatography (1.5×12 cm silica gel, linear gradient 1–9% MeOH/CH2Cl2

实验过程

To a solution of 0.049 g (0.09 mmol) [2-({[((2S)-1-{(2R)-2-[(tert-butoxycarbonyl) amino]-2-cyclohexylethanoyl} pyrrolidin-2-yl)carbonyl]amino} methyl)-4-chlorophenoxy]acetic acid (J. Med. Chem 1998, 41, 3210) in 3 mL DMF was added 0.018 g (0.1 mmol) glycine tertbutyl ester hydrochloride, 0.015 mL (0.1 mmol) triethylamine, 0.014 g (0.1 mmol) HOAt and 0.029 g (0.15 mmol) EDC. After 3 hours the reaction mixture was diluted with 100 mL EtOAc, washed with 50 mL each of 10% aqueous KHSO4, dilute brine, and brine, then dried over Na2SO4, filtered, and concentrated. The residue was dissolved in 3 mL CH2Cl2 and cooled to 0° C. whereupon 1.5 mL trifluoroacetic acid was added and the mixture stirred 30 minutes at 0° C. then warmed to room temperature for 2 hours. To this was added 50 mL toluene and the mixture concentrated, redissolved in CH2Cl2 and toluene and concentrated. The residue was dissolved in 50 mL DMF and to this was added 0.03 mL (0.2 mmol) triethylamine, 0.015 g (0.1 mmol) HOAt and 0.030 g (0.15 mmol) EDC. After 64 hours the reaction mixture was concentrated and the residue diluted with 50 mL EtOAc, washed with 20 mL each of 10% aqueous KHSO4, dilute brine, and brine, then dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography (1.5×12 cm silica gel, linear gradient 1–9% MeOH/CH2Cl2 afforded (6R,20aS)-16-chloro-6-cyclohexyl-2,3,6,7,9,10,18,19-octahydro-1H-pyrrolo[1,2-j][1,4,7,10,13] benzoxatetraazacyclohexadecine-5,8,11,20 (12H,20aH)-tetrone as a white flaky solid. 1H NMR (CD3OD, 400 MHz): δ 7.32 (d, J=2.65 Hz, 1H), 7.24 (dd, J=2.65 and 8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 4.75 (d, J=14.0 Hz, 1H), 4.69 (d, J=14.3 Hz, 1H), 4.60 (d, J=14.3 Hz, 1H); 4.45 (dd, J=3.2 and 8.5 Hz, 1H), 4.3 (d, J=9.97 Hz, 1H), 4.15 (d, J=15.6 Hz, 1H), 4.13 (d, J=14.0 Hz, 1H), 3.97 (m, 1H), 3.73 (d, J=15.6 Hz, 1H), 3.61 (m, 1H), 2.16 (m, 1H), 2.08 (m, 1H), 2.0–1.88 (m, 3H), 1.8–1.6 (m, 5H), 1.58 (m, 1H), 1.28 (m, 2H), 1.04 (m, 1H); exact mass calculated for C24H31C1N4O5: 491.2056 found 491.2067. Analytical HPLC (Zorbax SB-C18 4.6×75 mm, 5% to 95% CH3CN in 0.1% aqueous H3PO4):>99% at 215 nm.

来源