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Methanol → trans-4-[2-(4-Cyclobutylpiperazine-1-carbonyl)cyclopropyl]benzonitrile

HRID 572016
Notes
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Reaction equation

HRID 572016 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([OH:14])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:15](N(C(C)C)C(C)C)[CH3:16].CN(C(ON1N=[N:39][C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48]O>CN(C=O)C.C(Cl)Cl>[CH:37]1([N:38]2[CH2:33][CH2:34][N:39]([C:12]([C@@H:10]3[CH2:11][C@H:9]3[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[O:14])[CH2:16][CH2:15]2)[CH2:36][CH2:35][CH2:48]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 887MethanolHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67330003(1R,2R)-2-(4-cyanophenyl)cyclopropane-1-carboxylic acid

Product 1

HCID 25196788trans-4-[2-(4-Cyclobutylpiperazine-1-carbonyl)cyclopropyl]benzonitrile
Yield 68.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 21C (0.75 g, 4.01 mmol), 1-cyclobutylpiperazine, 2HCl (0.854 g, 4.01 mmol) and N-Ethyldiisopropylamine (2.79 mL, 16.03 mmol) in 20 ml of DMF at RT was added in portions HATU (1.523 g, 4.01 mmol). This was stirred for 60 min. then concentrated. The reaction was partitioned between EtOAc and 1 N HCl. The aq. layer was extracted 3× with EtOAc then made basic with 2 N NaOH. The aq. layer was extracted 3× with EtOAc and the combined organic layers were washed with brine then dried over MgSO4, filtered and concentrated. Purification was performed using a gradient of 0% to 10% MeOH in DCM. A second purification was necessary using first 100% EtOAc then 2-5% MeOH in DCM providing 0.853 g of 21D (68.8% yield).

Workup

  1. concentrationthen concentrated
  2. customThe reaction was partitioned between EtOAc and 1 N HCl
  3. extractionThe aq. layer was extracted 3× with EtOAc
  4. extractionThe aq. layer was extracted 3× with EtOAc
  5. washthe combined organic layers were washed with brine
  6. dry with materialthen dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification
  10. customA second purification

Sources & evidence

ORD record
ord-95b2629e9f784c58af4577a37387bcb8
Source dataset
uspto-grants-2015_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09029381B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes