1,2-Dichloroethane → (5S,11R)-22-chloro-11-cyclohexyl-18-oxa-3,9,12,15-tetrazatricyclo[17.4.0.05,9]tricosa-1(19),20,22-triene-4,10,13,16-tetrone

HRID 6687

반응식

HRID 6687 반응식
C([O:5][C:6]([NH:8][C@H:9]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]([NH:19][CH2:20][C:21]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:22]=1[O:23][CH2:24][C:25]([OH:27])=O)=[O:18])=[O:11])=O)(C)(C)C.Cl.C(OC(=O)[CH2:46][NH2:47])(C)(C)C.C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Cl:32][C:30]1[CH:29]=[CH:28][C:22]2[O:23][CH2:24][C:25](=[O:27])[NH:47][CH2:46][C:6](=[O:5])[NH:8][C@H:9]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:10](=[O:11])[N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[C:17](=[O:18])[NH:19][CH2:20][C:21]=2[CH:31]=1

참가 물질

8

반응물 5

HCID 111,2-Dichloroethane2회HCID 8471Triethylamine2회HCID 181649HOAt2회HCID 2725036Glycine tert-butyl ester hydrochlorideHCID 10745275[2-({[((2S)-1-{(2R)-2-[(tert-butoxycarbonyl) amino]-2-cyclohexylethanoyl} pyrrolidin-2-yl)carbonyl]amino} methyl)-4-chlorophenoxy]acetic acid

생성물 1

HCID 10435701(5S,11R)-22-chloro-11-cyclohexyl-18-oxa-3,9,12,15-tetrazatricyclo[17.4.0.05,9]tricosa-1(19),20,22-triene-4,10,13,16-tetrone

시약·촉매·용매 2

HCID 6228Dimethylformamide용매HCID 8857Ethyl Acetate용매

반응 조건

온도
0 °C

실험 절차

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.

후처리

  1. washwashed with 50 mL each of 10% aqueous KHSO4, dilute brine, and brine
  2. dry with materialdried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. dissolutionThe residue was dissolved in 3 mL CH2Cl2
  6. additionwas added
  7. temperaturethen warmed to room temperature for 2 hours
  8. additionTo this was added 50 mL toluene
  9. concentrationthe mixture concentrated
  10. dissolutionredissolved in CH2Cl2
  11. concentrationtoluene and concentrated
  12. dissolutionThe residue was dissolved in 50 mL DMF
  13. concentrationAfter 64 hours the reaction mixture was concentrated
  14. additionthe residue diluted with 50 mL EtOAc
  15. washwashed with 20 mL each of 10% aqueous KHSO4, dilute brine, and brine
  16. dry with materialdried over Na2SO4
  17. filtrationfiltered
  18. concentrationconcentrated
  19. customPurification by flash chromatography (1.5×12 cm silica gel, linear gradient 1–9% MeOH/CH2Cl2

출처 및 근거

ORD 기록
ord-a9969a0f2f7a4f47a1fe7d91077a1b28
출처 데이터셋
uspto-grants-2006_08
특허 번호
US07084134B2

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