Реакция #6783

Уравнение реакции

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

Растворители

EtOAc

DMF

Условия реакции

Обработка

1. 1
   Промывкаwashed with 50 mL each of 10% aqueous KHSO4, dilute brine, and brine
2. 2
   Сушкаdried over Na2SO4
3. 3
   Фильтрацияfiltered
4. 4
   Концентрированиеconcentrated
5. 5
   workup.DISSOLUTIONThe residue was dissolved in 3 mL CH2Cl2
6. 6
   workup.ADDITIONwas added
7. 7
   Температураthen warmed to room temperature for 2 hours
8. 8
   workup.ADDITIONTo this was added 50 mL toluene
9. 9
   Концентрированиеthe mixture concentrated
10. 10
    workup.DISSOLUTIONredissolved in CH2Cl2
11. 11
    Концентрированиеtoluene and concentrated
12. 12
    workup.DISSOLUTIONThe residue was dissolved in 50 mL DMF
13. 13
    КонцентрированиеAfter 64 hours the reaction mixture was concentrated
14. 14
    workup.ADDITIONthe residue diluted with 50 mL EtOAc
15. 15
    Промывкаwashed with 20 mL each of 10% aqueous KHSO4, dilute brine, and brine
16. 16
    Сушкаdried over Na2SO4
17. 17
    Фильтрацияfiltered
18. 18
    Концентрированиеconcentrated
19. 19
    ДругоеPurification by flash chromatography (1.5×12 cm silica gel, linear gradient 1–9% MeOH/CH2Cl2

Методика

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.

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