1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → Methyl 4-(1-(4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

HRID 541188Notes

Reaction equation

HRID 541188 reaction equation
[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH2:16][O:17][CH2:18][CH2:19][C:13]=2[N:12]=1.[CH3:20]CN=C=NCCCN(C)C.Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[CH3:20][C:44]1[CH:45]=[C:38]([CH:35]2[CH2:36][CH2:37][N:32]([C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]4[NH:15][C:14]5[CH2:16][O:17][CH2:18][CH2:19][C:13]=5[N:12]=4)[CH:4]=3)[CH2:33][CH2:34]2)[CH:39]=[CH:40][C:41]=1[C:42]#[N:43]

Participants

7

Reactant 3

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 193916184-(Piperidin-4-yl)benzonitrile--hydrogen chloride (1/1)2×HCID 682890224-Methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid2×

Product 1

HCID 68289233Methyl 4-(1-(4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrileYield 34%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid (compound 1.11, 60 mg, 0.22 mmol, 1.00 equiv, 95%), EDCI (88.4 mg, 0.46 mmol, 2.00 equiv), DMAP (85.12 mg, 0.70 mmol, 3.00 equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 52 mg, 0.23 mmol, 1.00 equiv) in DMF was stirred at room temperature. After 3 h, the reaction mixture was diluted with 40 mL of DCM and washed with 2×10 mL of NH4Cl (aq.sat.) followed by 2×10 mL of brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude product (˜100 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18, 19*150 mm Sum; mobile phase, WATER WITH 0.05% TFA and CH3CN (15.0% CH3CN up to 42.0% in 12 min, up to 100.0% in 1 min); Detector, uv 254/220 nm. The fractions containing pure compound were combined and lyophilized to yield 32.9 mg (34%) of the title compound as a white solid. m/z (ES+) 427 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.73-7.65 (m, 4H), 7.61 (d, J=5.7 Hz, 1H), 7.50 (d, J=6.0 Hz, 2H), 4.89-4.78 (1H partially obscured by water peak), 4.81 (s, 2H), 4.10 (t, J=4.1 Hz, 2H), 3.94-3.81 (m, 1H), −3.35 (1H partially obscured by methanol solvent peak), 3.08-1.95 (m, 2H), 2.92 (t, J=4.1 Hz, 2H), 2.52 (s, 3H), 2.08-1.92 (m, 1H), 1.92-1.65 (m, 3H). 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.30 (s, 1H) 7.50 (m, 2H), 4.89 (d, J=13.0 Hz, 1H), 4.81 (s, 2H), 4.05 (t, J=5.2 Hz, 2H), 3.77 (d, J=13.2 Hz, 1H), 3.30 (t, J=13.0 Hz, 1H), 3.01-2.84 (m, 4H), 2.34 (s, 3H), 2.06 (d, J=13.7 Hz, 1H), 1.86 (d, J=12.9 Hz, 1H), 1.76 (q, J=12.8 Hz, 1H), 1.57 (q, J=11.7 Hz, 1H).

Workup

  1. washwashed with 2×10 mL of NH4Cl (aq.sat.)
  2. dry with materialThe organic layer was dried (Na2SO4)
  3. concentrationconcentrated under reduced pressure
  4. customThe crude product (˜100 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters))
  5. waitmobile phase, WATER WITH 0.05% TFA and CH3CN (15.0% CH3CN up to 42.0% in 12 min
  6. waitup to 100.0% in 1 min)
  7. additionThe fractions containing pure compound

Sources & evidence

ORD record
ord-e0b27cb9294645d696f05c0ee8d8aaff
Source dataset
uspto-grants-2014_10
Patent number
US08871790B2

Reaction notes

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