Diisopropylethylamine → (2R,5S)-4-{2-[6-(4-Fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester

HRID 1475513Notes

Reaction equation

HRID 1475513 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([OH:25])=O)[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:45]=[CH:44][C:31]([CH2:32][C:33]2[CH:34]=[C:35]3[NH:41][CH2:40][C:39]([CH3:43])([CH3:42])[C:36]3=[N:37][CH:38]=2)=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:41]2[C:35]3[C:36](=[N:37][CH:38]=[C:33]([CH2:32][C:31]4[CH:44]=[CH:45][C:28]([F:27])=[CH:29][CH:30]=4)[CH:34]=3)[C:39]([CH3:43])([CH3:42])[CH2:40]2)=[O:25])[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:3])([CH3:4])[CH3:2]

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 709806526-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridineHCID 70980770(2R,5S)-4-Carboxymethyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester

Product 1

HCID 70980911(2R,5S)-4-{2-[6-(4-Fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl esterYield 77.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To (2R,5S)-4-carboxymethyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 4.04 mmol) and 6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1.14 g, 4.4 mmol) in DMF (20.2 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.31 g, 6.1 mmol) and N,N-diisopropylethylamine (1.41 mL, 8.1 mmol) at room temperature. The reaction was stirred at room temperature for 18 h, then saturated aqueous sodium hydrogen carbonate was added and the mixture extracted with diethyl ether (3×). The combined organic extracts were washed with water (3×) and brine (3×), then dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (1.9 g, 77%), MS: [M+H]+=610.

Workup

  1. extractionthe mixture extracted with diethyl ether (3×)
  2. washThe combined organic extracts were washed with water (3×) and brine (3×)
  3. dry with materialdried with sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. washChromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60)

Sources & evidence

ORD record
ord-cc889a35969b46a99b08636dd837f445
Source dataset
uspto-grants-2015_04
Patent number
US09018214B2

Reaction notes

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