Sodium Acetate → 5-(4-chlorophenyl)-5-(3-{4-[1-(3,3-difluoropyrrolidin-1-yl)ethyl]piperidin-1-yl}-3-oxopropyl)-5H-imidazo[2,1-a]isoindole

HRID 46174Notes

Reaction equation

HRID 46174 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([C:30](=O)[CH3:31])[CH2:26][CH2:25]3)=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1.[Cl-].[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH2+:37][CH2:36]1.CC([O-])=O.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:20][CH2:21][C:22]([N:24]3[CH2:25][CH2:26][CH:27]([CH:30]([N:37]4[CH2:38][CH2:39][C:35]([F:40])([F:34])[CH2:36]4)[CH3:31])[CH2:28][CH2:29]3)=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 517045Sodium AcetateHCID 27828263,3-Difluoropyrrolidine, chlorideHCID 5049666Sodium triacetoxyborohydrideHCID 58415640HCID 58415640, compound

Product 1

HCID 566664195-(4-chlorophenyl)-5-(3-{4-[1-(3,3-difluoropyrrolidin-1-yl)ethyl]piperidin-1-yl}-3-oxopropyl)-5H-imidazo[2,1-a]isoindole

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent

Procedure

To a mixture of 1-(1-{3-[5-(4-chlorophenyl)-5H-imidazo[2,1-a]isoindol-5-yl]propanoyl}piperidin-4-yl)ethanone (27 mg), 3,3-difluoropyrrolidinium chloride (17 mg) and NaOAc (15 mg) in CH2Cl2 was added AcOH (0.01 mL). After stirring the resulting mixture for 30 minutes NaBH(OAc)3 (26 mg) was added and allowed to stir overnight. The reaction mixture was then partitioned between saturated aqueous NaHCO3 and CH2Cl2. Aqueous layer was extracted with CH2Cl2 (2×). Combined organic layers were dried over Na2SO4 and concentrated. Purification by reversed phase HPLC (21×100 mm Phenomenex Gemini, 15-95% MeCN/water containing 0.05% NH4OH over 20 min at 20 mL/min) afforded title compound as a white solid. HRMS. Found, 539.2387; calcd for (M+H)+, 539.2384. 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J=7.62 Hz, 1 H); 7.43-7.38 (m, 1 H); 7.35-7.26 (m, 4 H); 7.25-7.19 (m, 1 H); 7.11 (d, J=8.36 Hz, 2 H); 6.96 (d, J=9.03 Hz, 1 H); 4.54 (d, J=13.34 Hz, 1 H); 3.31 (d, J=13.41 Hz, 1 H); 3.11-3.03 (m, 1 H); 2.91-2.80 (m, 3 H); 2.76-2.61 (m, 3 H); 2.38-2.13 (m, 4 H); 1.69-1.50 (m, 6 H); 0.90-0.83 (m, 4 H).

Workup

  1. additionwas added
  2. customThe reaction mixture was then partitioned between saturated aqueous NaHCO3 and CH2Cl2
  3. extractionAqueous layer was extracted with CH2Cl2 (2×)
  4. dry with materialCombined organic layers were dried over Na2SO4
  5. concentrationconcentrated
  6. customPurification by reversed phase HPLC (21×100 mm Phenomenex Gemini, 15-95% MeCN/water containing 0.05% NH4OH over 20 min at 20 mL/min)

Sources & evidence

ORD record
ord-cf58ac05f7324b8b80f17e90c1c31663
Source dataset
uspto-grants-2013_09
Patent number
US08541595B2

Reaction notes

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