Diethylamine → ((r)-2-{(s)-2-[(r)-2-(9h-Fluoren-9-ylmethoxycarbonylamino)-3-methyl-butyrylamino]-3-tritylsulfanyl-propionylamino}-3-methyl-butyrylamino)-acetic acid methyl ester

HRID 1012860

Reaktionsgleichung

Reaktionsgleichung von HRID 1012860
[CH3:1][O:2][C:3](=[O:55])[CH2:4][NH:5][C:6](=[O:54])[C@H:7]([NH:11][C:12](=[O:53])[C@H:13](NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:14][S:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:8]([CH3:10])[CH3:9].[NH:56](CC)CC.[C:61]([NH:78][C@@H:79]([C:83](O)=[O:84])[CH:80]([CH3:82])[CH3:81])([O:63][CH2:64][CH:65]1[C:77]2[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=2)[C:71]2[C:66]1=[CH:67][CH:68]=[CH:69][CH:70]=2)=[O:62].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC#N.C(Cl)Cl.CCCCCCC.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:55])[CH2:4][NH:5][C:6](=[O:54])[C@H:7]([NH:11][C:12](=[O:53])[C@H:13]([NH:56][C:83](=[O:84])[C@H:79]([NH:78][C:61]([O:63][CH2:64][CH:65]1[C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][C:71]=2[C:72]2[C:77]1=[CH:76][CH:75]=[CH:74][CH:73]=2)=[O:62])[CH:80]([CH3:82])[CH3:81])[CH2:14][S:15][C:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:8]([CH3:9])[CH3:10]

Komponenten

10

Edukt 6

HCID 8021DiethylamineHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 1549479(2R)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-methylbutanoic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 57696983{(R)-2-[(S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionylamino]-3-methyl-butyrylamino}-acetic acid methyl ester

Produkt 1

HCID 67313819((r)-2-{(s)-2-[(r)-2-(9h-Fluoren-9-ylmethoxycarbonylamino)-3-methyl-butyrylamino]-3-tritylsulfanyl-propionylamino}-3-methyl-butyrylamino)-acetic acid methyl esterAusbeute 78 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 6344DichloromethaneLösungsmittel2×HCID 8900HeptaneLösungsmittelHCID 21877088Acetonitrile methylene chlorideLösungsmittel

Versuchsvorschrift

To a stirred solution of 3A (836 mg, 1.11 mmol) in CH3CN/CH2Cl2 (1:1, 60 mL) at RT was added Et2NH (3 mL). After stirring for 3 h at RT the reaction mixture was diluted with heptane (60 mL) and concentrated to give the crude amine as a colourless oil. To a stirred solution of Fmoc-D-valine (577 mg, 1.7 mmol) in CH2Cl2 (40 mL) was added EDAC.HCl (326 mg, 1.7 mmol), HOBt (230 mg, 1.7 mmol) and DIEA (627 μl, 3.6 mmol). After stirring at RT for 10 minutes a solution of the crude amine in CH2Cl2 (20 mL) was then added and the reaction mixture stirred for 12 h. Whereupon the reaction was washed with water (15 mL), 10% HCl (15 mL), 5% NaHCO3 (15 mL) and sat NaCl (15 mL) solutions, dried (Na2SO4), filtered, and the solvent removed to give an off white solid which was recrystallised from CH3CN to give 4C as a white solid (734 mg, 0.86 mmol, 78%): 1H-NMR (400 MHz, CDCl3) δ 7.74 (d, J=7.5 Hz, 2H), 7.53 (t, J=7.5 Hz, 2H), 7.42-7.32 (m, 9H), 7.30-7.19 (m, 9H), 7.16 (t, J=7.0 Hz, 2H), 6.80 (d, J=8.0 Hz, 1H), 6.57 (d, J=7.0 Hz, 1H), 5.52 (d, J=8.0 Hz, 1H), 4.44 (t, J=8.0 Hz, 1H), 4.38 (dd, J=10.5, 7.5 Hz, 1H), 4.25 (dd, J=10.5, 7.0 Hz, 1H), 4.17-3.95 (m, 3H), 3.87 (dd, J=18.1, 5.5 Hz, 1H), 3.78 (dd, J=18.1, 5.5 Hz, 1H), 3.63 (s, 3H), 2.71 (dd, J=12.5, 6.0 Hz, 1H), 2.53 (dd, J=12.5, 6.0 Hz, 1H), 2.21 (sept, J=6.4 Hz, 1H), 2.07-1.93 (m, 1H), 0.93-0.83 (m, 12H); 13C NMR 100 MHz 171.5 (C), 171.1 (C), 170.2 (2×C), 156.6 (C), 144.4 (C), 144.0 (C), 143.8 (C), 141.4 (C), 129.6 (CH), 128.3 (CH), 127.9 (CH), 127.2 (CH), 127.1 (CH), 125.2 (CH), 120.1 (CH), 67.3 (CH2), 67.2 (C), 60.3 (CH), 58.5 (CH), 52.5 (CH), 52.3 (CH), 47.3 (CH), 41.0 (CH2), 33.8 (CH2), 31.5 (CH), 30.5 (CH), 19.2 (2×CH3), 18.0 (CH3), 17.8 (CH3); LRMS (ES+) m/z 1832 (10%, [2M+Na]+), 877.5 (100%, [M+Na]+).

Aufarbeitung

  1. concentrationconcentrated
  2. customto give the crude amine as a colourless oil
  3. additionwas then added
  4. stirringthe reaction mixture stirred for 12 h
  5. washWhereupon the reaction was washed with water (15 mL), 10% HCl (15 mL), 5% NaHCO3 (15 mL)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. customthe solvent removed
  9. customto give an off white solid which
  10. customwas recrystallised from CH3CN

Quellen und Nachweise

ORD-Eintrag
ord-2c40d57ce8c343b4b1ddcba07d9dd40a
Quelldatensatz
uspto-grants-2011_07
Patentnummer
US07977304B2

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