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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 1034852
Notes
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Reaction equation

HRID 1034852 reaction equation
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
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

10

Reactant 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

Product 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
Yield 89%

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 13387N-methyl-2-pyrrolidoneSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-6546b86a066943539c5461f97f9d37e2
Source dataset
uspto-grants-2013_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08545897B2

Reaction notes

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