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Triethylamine → 2-[1-(Biphenyl-4-carbonyl)-pyrrolidin-2-yl]-5-(4-tert-butoxycarbonylamino-pyridin-3-yl)-pent-4-ynoic acid methyl ester

HRID 901326
Notes
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Reaction equation

HRID 901326 reaction equation
[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:14])[CH2:5][C:6]#[CH:7].[C:28]([O:32][C:33](=[O:42])[NH:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1I)([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.CN(C=O)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]#[C:7][C:40]1[CH:39]=[N:38][CH:37]=[CH:36][C:35]=1[NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:42]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 10903275(3-Iodo-pyridin-4-yl)-carbamic acid tert-butyl esterHCID 865880852-[1-(Biphenyl-4-carbonyl)-pyrrolidin-2-yl]-pent-4-ynoic acid methyl ester

Product 1

HCID 692528602-[1-(Biphenyl-4-carbonyl)-pyrrolidin-2-yl]-5-(4-tert-butoxycarbonylamino-pyridin-3-yl)-pent-4-ynoic acid methyl ester

Reagents, catalysts & solvents 3

HCID 83717
Copper iodide
Catalyst
HCID 178418476HCID 178418476, compoundCatalyst
HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A flask is charged with 2-[1-(Biphenyl-4-carbonyl)-pyrrolidin-2-yl]-pent-4-ynoic acid methyl ester (0.58 g, 1.62 mmol), (3-iodopyridin-4-yl)-carbamic acid tert-butyl ester (0.52 g, 1.62 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.057 g, 0.081 mmol), copper iodide (0.0104 g, 0.055 mmol), triethylamine (0.90 mL, 6.5 mmol) and DMF (7.3 mL) and heated at 90° C. for 2 h. The reaction is cooled to RT and partitioned between EtOAc (200 mL) and saturated sodium bicarbonate (75 mL). The organic layer is washed with saturated sodium bicarbonate (2×75 mL), brine (50 mL), dried over MgSO4 and concentrated. The residue is subjected to flash chromatography (1:1/EtOAc:hexanes) to give 2-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-yl]-5-(4-tert-butoxycarbonylamino-pyridin-3-yl)-pent-4-ynoic acid methyl ester as an impure mixture (0.35 g, three components) which is used without further purification. This material (0.35 g, 0.63 mmol estimated), DBU (0.19 g, 1.26 mmol) and acetonitrile (7 mL) is stirred at 50° C. for 6 h. The reaction mixture is concentrated and purified by flash chromatography (0.5% MeOH/CH2Cl2) to (2.0% MeOH/CH2Cl2) to give the title compound (0.18 g, 0.325 mmol). 1H NMR (CDCl3, 300 MHz) 8.83(s, 1H), 8.41(m, 1H), 8.25(d, 1H), 7.65-7.53(m, 6H), 7.52-7.32(m, 3H), 6.80(s, 1H), 4.84-4.68(m, 1H), 3.73, 3.68(two s, 3H), 3.67-3.35(m, 6H), 2.21-1.91(m, 4H), 1.67(s, 9H).

Workup

  1. temperatureThe reaction is cooled to RT
  2. custompartitioned between EtOAc (200 mL) and saturated sodium bicarbonate (75 mL)
  3. washThe organic layer is washed with saturated sodium bicarbonate (2×75 mL), brine (50 mL)
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-fff12119c10849d7b8861deadfd3a438
Source dataset
uspto-grants-2008_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07361663B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes