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Sodium Carbonate → HCID 72548394, Verbindung

HRID 2206433
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[Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39](O)=[O:40])=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:81][C@@H:82]([CH2:93][CH2:94][C:95]([O:97][CH2:98][C:99]1[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=1)=[O:96])[C:83]([O:85][CH2:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[O:84].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:86]([O:85][C:83](=[O:84])[C@@H:82]([NH:81][C:39](=[O:40])[CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)[CH2:93][CH2:94][C:95]([O:97][CH2:98][C:99]1[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=1)=[O:96])[C:87]1[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=1
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Komponenten

7

Edukt 5

HCID 10340Sodium CarbonateHCID 81531Diisopropylethylamine2×HCID 199613(S)-Dibenzyl 2-aminopentanedioate hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 72548393HCID 72548393, Verbindung

Produkt 1

HCID 72548394HCID 72548394, VerbindungAusbeute 33 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel2×

Versuchsvorschrift

In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)-acetic acid (Example 69, 133 mg, 197 μmol), HATU (75.0 mg, 197 μmol) and Hunig's base (51.0 mg, 68.9 μL, 394 μmol) were combined with dry tetrahydrofuran (1 mL) to give an off-white suspension at room temperature. The mixture was stirred for 30 min and a solution of (S)-dibenzyl 2-aminopentanedioate hydrochloride (108 mg, 296 μmol) and Hunig's base (2 eq.) in dry tetrahydrofuran (1 mL) was added. After 1 h, the reaction mix was directly purified with reverse phase high-performance liquid chromatography to isolate the desired fraction, which was neutralized with saturated aqueous sodium carbonate solution, extracted with methylene chloride. The methylene chloride layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-2-[2-(4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoyloxy)-acetylamino]-pentanedioic acid dibenzyl ester (63 mg, 33% yield). LCMS (ES+) m/z calcd. for C52H51Cl2F2N4O9 [(M+H)+]: 983. found: 983.

Aufarbeitung

  1. customto give an off-white suspension at room temperature
  2. waitAfter 1 h
  3. additionthe reaction mix
  4. customwas directly purified with reverse phase high-performance liquid chromatography
  5. customto isolate the desired fraction, which
  6. extractionextracted with methylene chloride
  7. washThe methylene chloride layer was washed with water and brine
  8. dry with materialdried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated

Quellen und Nachweise

ORD-Eintrag
ord-ec2f52d8374a4990be11fa1b8f11e8ca
Quelldatensatz
uspto-grants-2016_06
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09371280B2

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