Diisopropylethylamine → Methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate

HRID 541351Notes

Reaction equation

HRID 541351 reaction equation
[CH:1]1([C:5]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH2:18][CH3:19])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:54][C:55]1([C:61]2[CH:68]=[CH:67][C:64]([C:65]#[N:66])=[CH:63][CH:62]=2)[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C)C=O>[C:65]([C:64]1[CH:67]=[CH:68][C:61]([C:55]2([F:54])[CH2:60][CH2:59][N:58]([C:9]([C:8]3[C:7]([CH2:18][CH3:19])=[CH:6][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[C:13]([CH:12]=3)[C:14]([O:16][CH3:17])=[O:15])=[O:10])[CH2:57][CH2:56]2)=[CH:62][CH:63]=1)#[N:66]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 682888554-(4-Fluoropiperidin-4-yl)benzonitrile hydrochloride2×HCID 682889334-Cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid2×

Product 1

HCID 68288689Methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoateYield 84%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a round-bottom flask was added a solution of 4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4, 70.0 mg, 0.270 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). HBTU (210 mg, 0.550 mmol, 2.07 equiv), DIEA (150 mg, 1.16 mmol, 4.35 equiv) were added to the reaction mixture at 0° C., and stirred for 30 min. This was followed by the addition of 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2 HCl salt, 80.0 mg, 0.330 mmol, 1.20 equiv). The resulting solution was stiffed for 15 h at 25° C., and then quenched with 20 mL of ice-water. The mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 1×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:5) as eluent to yield 100 mg (84%) of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate as a white solid.

Workup

  1. waitThe resulting solution was stiffed for 15 h at 25° C.
  2. customquenched with 20 mL of ice-water
  3. extractionThe mixture was extracted with 2×50 mL of ethyl acetate
  4. washThe combined organic layers were washed with 1×50 mL of brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified

Sources & evidence

ORD record
ord-4e8bbe5c510649f8b7f0707b9636dc2c
Source dataset
uspto-grants-2014_10
Patent number
US08871790B2

Reaction notes

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