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Lithium Hydroxide → (R)-tert-butyl 1-(5-chloro-3-(2-hydroxy-2-methylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate

HRID 408367
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Reaktionsgleichung

Reaktionsgleichung von HRID 408367
C([O:4][C:5]([CH3:10])([CH3:9])[C:6](Cl)=[O:7])(=O)C.[NH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([Cl:35])[C:19]=2[N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]2)[NH:14][CH:13]=1.C(N(CC)CC)C.[Li+].[OH-]>ClCCl.CN1C(=O)CCC1.O.CC#N.O.C1COCC1>[Cl:35][C:18]1[C:19]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:22]2)=[C:20]2[C:12]([NH:11][C:6](=[O:7])[C:5]([OH:4])([CH3:10])[CH3:9])=[CH:13][NH:14][C:15]2=[N:16][CH:17]=1
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Komponenten

10

Edukt 4

HCID 3939Lithium HydroxideHCID 8471TriethylamineHCID 1234962-Acetoxyisobutyroyl chlorideHCID 67045610(R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate

Produkt 1

HCID 67045520(R)-tert-butyl 1-(5-chloro-3-(2-hydroxy-2-methylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate
Ausbeute 89 %

Reagenzien, Katalysatoren, Lösungsmittel 5

HCID 962WaterLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 8028TetrahydrofuranLösungsmittelHCID 13387N-methyl-2-pyrrolidoneLösungsmittelHCID 18373917Acetonitrile--water (1/1)Lösungsmittel

Versuchsvorschrift

A solution of 1-chloro-2-methyl-1-oxopropan-2-yl acetate (540 mg, 0.469 mL, 3.28 mmol) in anhydrous dichloromethane (2 mL) was added dropwise to a solution of (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (200 mg, 547 mmol; Example 91, Step A) and triethylamine (387 mg, 0.533 mL, 3.83 mmol) in NMP (15 mL) cooled on an ice-bath. The mixture was stirred at ambient temperature for 2 hours. THF (10 mL) was added. The mixture treated with an aqueous solution of 2N LiOH (10 mL) and stirred overnight. The mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-75% CH3CN/water, 25CV) to give (R)-tert-butyl 1-(5-chloro-3-(2-hydroxy-2-methylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (221 mg, 89% yield) as a solid. LCMS (APCI+) m/z 452, 454 (M+H)+, Retention time=3.44 minutes.

Aufarbeitung

  1. temperaturecooled on an ice-bath
  2. stirringstirred overnight
  3. extractionextracted with EtOAc (3×30 mL)
  4. dry with materialThe combined organic extracts were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by reverse phase chromatography (Biotage SP4

Quellen und Nachweise

ORD-Eintrag
ord-17cbabbc743a41b69344eba972c87d62
Quelldatensatz
uspto-grants-2014_06
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08758830B2

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