Diisopropylethylamine → (S)-4-(1-(2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

HRID 541405Notes

Reaction equation

HRID 541405 reaction equation
[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([N:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1)=[O:6]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 193916184-(Piperidin-4-yl)benzonitrile--hydrogen chloride (1/1)2×HCID 68288792(S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate2×

Product 1

HCID 68289156(S)-4-(1-(2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrileYield 15.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

To a round-bottom flask was added a solution of (S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate (compound 257.4, 143 mg, 0.500 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). HBTU (285 mg, 0.750 mmol, 1.50 equiv) was added to the reaction, and it was stiffed for 30 min at 25° C. To this was added 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 133 mg, 0.600 mmol, 1.20 equiv) and DIEA (390 mg, 3.02 mmol, 6.04 equiv) dropwise. The resulting solution was stirred for 30 min at 25° C., then quenched with 20 mL of water. The mixture was extracted with 3×25 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with methanol/ethyl acetate (1:30) as eluent. The product (˜100 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (35% CH3CN up to 52% in 8 min, up to 100% in 1 min, down to 35% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 34.6 mg (15%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+.

Workup

  1. customquenched with 20 mL of water
  2. extractionThe mixture was extracted with 3×25 mL of ethyl acetate
  3. dry with materialthe combined organic layers were dried over anhydrous sodium sulfate
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified
  6. customThe product (˜100 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU))
  7. waitmobile phase, water with 0.03% NH3H2O and CH3CN (35% CH3CN up to 52% in 8 min
  8. waitup to 100% in 1 min
  9. waitdown to 35% in 1 min)
  10. additionThe fractions containing pure compound

Sources & evidence

ORD record
ord-573aeccb7a7e4e5ba8444b94fea29ff9
Source dataset
uspto-grants-2014_10
Patent number
US08871790B2

Reaction notes

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