1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → 4-(1-(2,4-Dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

HRID 541477Notes

Reaction equation

HRID 541477 reaction equation
[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]3[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][C:14]=3[N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.Cl.[NH:35]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]3[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][C:14]=3[N:13]=2)=[CH:7][C:3]=1[C:4]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1)=[O:6]

Participants

6

Reactant 3

HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 193916184-(Piperidin-4-yl)benzonitrile--hydrogen chloride (1/1)2×HCID 682889362,4-Dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid

Product 1

HCID 682891874-(1-(2,4-Dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrileYield 10.4%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

Into around-bottom flask, was placed a solution of 2,4-dimethyl-5-[6-methyl-3H,4H,6H,7H-pyrano[3,4-d]imidazol-2-yl]benzoic acid (50 mg, 0.17 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). EDC.HCl (67 mg, 0.35 mmol, 2.00 equiv), 4-dimethylaminopyridine (64 mg, 0.52 mmol, 3.00 equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 39 mg, 0.18 mmol, 1.00 equiv) were added and the solution was stiffed for 2 h at room temperature. The reaction was quenched with water (20 mL) and the aqueous was extracted with ethyl acetate (2×20 mL). The combined organics was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1) as the eluent. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep Phenyl, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (30% CH3CN up to 60% in 9 min, up to 100% in 1 min, down to 30% in 1 min); Detector, Waters 2489 254 nm & 220 nm. The fractions containing pure product were combined and lyophilized to obtain the title compound as a white solid (8.0 mg, 10%). m/z (ES+) 455 (M+H)+.

Workup

  1. customInto around-bottom flask, was placed
  2. customThe reaction was quenched with water (20 mL)
  3. extractionthe aqueous was extracted with ethyl acetate (2×20 mL)
  4. dry with materialThe combined organics was dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1) as the eluent
  8. customThe crude product (20 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU))
  9. waitmobile phase, water with 0.03% NH3H2O and CH3CN (30% CH3CN up to 60% in 9 min
  10. waitup to 100% in 1 min
  11. waitdown to 30% in 1 min)
  12. additionThe fractions containing pure product

Sources & evidence

ORD record
ord-2d138fca8e664d1ca128dc121ee7c876
Source dataset
uspto-grants-2014_10
Patent number
US08871790B2

Reaction notes

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