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

HRID 1475508Notes

Reaction equation

HRID 1475508 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[N:11]([CH2:21][C:22](O)=[O:23])[CH2:10][C@H:9]1[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([C:31]1[CH:32]=[C:33]2[NH:39][CH2:38][C:37]([CH3:41])([CH3:40])[C:34]2=[N:35][CH:36]=1)([F:30])[CH2:28][CH3:29].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.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[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[N:11]([CH2:21][C:22]([N:39]2[C:33]3[C:34](=[N:35][CH:36]=[C:31]([C:27]([F:30])([F:26])[CH2:28][CH3:29])[CH:32]=3)[C:37]([CH3:40])([CH3:41])[CH2:38]2)=[O:23])[CH2:10][C@H:9]1[CH3:25])=[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 709806426-(1,1-Difluoro-propyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridineHCID 70981057(2R,5S)-4-Carboxymethyl-2-methyl-5-(2-oxo-pyrrolidin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester

Product 1

HCID 70980486(2R,5S)-4-{2-[6-(1,1-Difluoro-propyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-(2-oxo-pyrrolidin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl esterYield 56.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(2R,5S)-4-Carboxymethyl-2-methyl-5-(2-oxo-pyrrolidin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.20 g, 0.56 mmol) and 6-(1,1-difluoro-propyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (0.15 g, 0.6 mmol) were dissolved in DMF (2.8 mL). N,N-Diisopropylethylamine (0.36 g, 2.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.43 g, 1.1 mmol) were added and the reaction stirred at room temperature for 18 h. Saturated aqueous sodium bicarbonate (10 mL) was added and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic extracts were diluted with petroleum spirit (20 mL), washed with water (3×), dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-5%, methanol in EtOAc) gave the title compound (0.178 g), MS: [M+H]+=564.

Workup

  1. extractionthe aqueous phase extracted with EtOAc (3×10 mL)
  2. additionThe combined organic extracts were diluted with petroleum spirit (20 mL)
  3. washwashed with water (3×)
  4. dry with materialdried with sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. washChromatography (silica gel, gradient elution, 0-5%, methanol in EtOAc)

Sources & evidence

ORD record
ord-a20e8f9ef24a4de792e81d5d2aba744b
Source dataset
uspto-grants-2015_04
Patent number
US09018214B2

Reaction notes

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