1,1'-Carbonyldiimidazole → (2R,5S)-4-{2-[6-(2,4-Difluoro-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 1475519Notes

Reaction equation

HRID 1475519 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].C(N1C=CN=C1)(N1C=CN=C1)=O.[F:39][C:40]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:41]=1[CH2:42][C:43]1[CH:44]=[C:45]2[NH:51][CH2:50][C:49]([CH3:53])([CH3:52])[C:46]2=[N:47][CH:48]=1>C(Cl)Cl>[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:51]2[C:45]3[C:46](=[N:47][CH:48]=[C:43]([CH2:42][C:41]4[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:40]=4[F:39])[CH:44]=3)[C:49]([CH3:53])([CH3:52])[CH2:50]2)=[O:25])[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:3])([CH3:4])[CH3:2]

Participants

5

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 709802076-(2,4-Difluoro-benzyl)-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 70980577(2R,5S)-4-{2-[6-(2,4-Difluoro-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 51.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
20 °C

Procedure

A mixture of (2R,5S)-4-carboxymethyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.32 mmol), 1,1′-carbonyldiimidazole (0.057 g, 0.35 mmol) and DCM (5 mL) was stirred at 20° C. for 24 h. 6-(2,4-Difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (0.088 g, 0.32 mmol) was added and the mixture heated at 35° C. for 24 h. Solvent was evaporated and the residue dissolved in 1,2-dichloroethane and the mixture was heated to 60° C. for 24 h. Mixture was partitioned between saturated aqueous NaHCO3 (30 mL) and DCM (3×20 mL) and combined organic extracts were dried and evaporated to give an oil. Chromatography (SiO2, gradient elution, 0-100% EtoAc in petrol 40-60) gave the title compound (0.103 g) as an oil. MS: [M+H]+=628.

Workup

  1. temperaturethe mixture heated at 35° C. for 24 h
  2. customSolvent was evaporated
  3. dissolutionthe residue dissolved in 1,2-dichloroethane
  4. temperaturethe mixture was heated to 60° C. for 24 h
  5. customMixture was partitioned between saturated aqueous NaHCO3 (30 mL) and DCM (3×20 mL)
  6. customwere dried
  7. customevaporated
  8. customto give an oil
  9. washChromatography (SiO2, gradient elution, 0-100% EtoAc in petrol 40-60)

Sources & evidence

ORD record
ord-b7fefb1ef0b1413cba18bbc34f1b925d
Source dataset
uspto-grants-2015_04
Patent number
US09018214B2

Reaction notes

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