Diisopropylethylamine → 4-(1-(4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

HRID 541326Notes

Reaction equation

HRID 541326 reaction equation
[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][CH:17]=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:19])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:21][C:22]1([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][CH:17]=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:25]3[CH2:26][CH2:27][C:22]([C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=4)([F:21])[CH2:23][CH2:24]3)=[O:11])=[C:7]([CH3:19])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 682888554-(4-Fluoropiperidin-4-yl)benzonitrile hydrochloride2×HCID 178422590HCID 178422590, compound2×

Product 1

HCID 1784225894-(1-(4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrileYield 56.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a 4-mL vial was added 4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid (compound 202.3, 31 mg, 0.12 mmol, 1.0 equiv), 4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 31 mg, 0.13 mmol, 1.1 equiv), 1-hydroxybenzotriazole hydrate (20 wt % water) (25 mg, 0.15 mmol, 1.25 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg, 0.13 mmol, 1.1 equiv), DMF (0.6 mL) and DIEA (83 μL, 0.48 mmol, 4 equiv). The mixture was stiffed at room temperature for 4 hours then diluted with ethyl acetate (10 mL) and washed with 1 M NaH2PO4 (5 mL). The aqueous was back extracted with ethyl acetate (3 mL) and the combined organics was washed with brine (5 mL), saturated NaHCO3 (5 mL) and brine (5 mL). The organics were dried (Na2SO4), filtered and removed in vacuo. The crude residue was purified by preparative TLC (DCM/8% MeOH) to obtain the title compound as a white solid (30 mg, 56%). m/z (ES+) 444 (M+H)+.

Workup

  1. washwashed with 1 M NaH2PO4 (5 mL)
  2. extractionThe aqueous was back extracted with ethyl acetate (3 mL)
  3. washthe combined organics was washed with brine (5 mL), saturated NaHCO3 (5 mL) and brine (5 mL)
  4. dry with materialThe organics were dried (Na2SO4)
  5. filtrationfiltered
  6. customremoved in vacuo
  7. customThe crude residue was purified by preparative TLC (DCM/8% MeOH)

Sources & evidence

ORD record
ord-9793ce43ba9a424290d0eb722a1a5192
Source dataset
uspto-grants-2014_10
Patent number
US08871790B2

Reaction notes

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