1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → 4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

HRID 541399Notes

Reaction equation

HRID 541399 reaction equation
[CH:1]1([C:5]2[C:13]([C:14]3[NH:15][C:16]([CH2:19][O:20][CH3:21])=[CH:17][N:18]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH:1]1([C:5]2[C:13]([C:14]3[NH:15][C:16]([CH2:19][O:20][CH3:21])=[CH:17][N:18]=3)=[CH:12][C:8]([C:9]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1

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 682888074-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acid2×

Product 1

HCID 665483184-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrileYield 25.6%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

To a round-bottom flask was added a solution of 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acid (compound 246.4, 50.0 mg, 0.150 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (3 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 41.0 mg, 0.170 mmol, 1.10 equiv), EDC.HCl (64.0 mg, 0.330 mmol, 2.00 equiv), and 4-dimethylaminopyridine (41.0 mg, 0.340 mmol, 2.00 equiv) were added to the reaction. The resulting solution was stirred for 3 h at 25° C., then quenched with water and extracted with 2×30 mL of ethyl acetate. The combined organic layers were concentrated in vacuo. The crude product (˜50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (26.0% CH3CN up to 42.0% in 7 min, up to 100.0% in 2 min, down to 26.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 18 mg (25%) of the title compound as a white solid. m/z (ES+) 469 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.73-7.64 (m, 3H), 7.52-7.32 (m, 4H), ˜4.9 (1H partially obscured by water peak), 4.60 (s, 2H), 3.81-3.68 (m, 1H), 3.68-3.52 (m, 1H), 3.46 (s, 3H), 3.35-3.22 (m, 1H partially obscured by methanol solvent peak), 3.09-2.95 (m, 2H), 2.52 & 2.41 (2 singlets, amide rotamers, Ar—CH3, 3H), 2.16-1.97 (m, 6H), 1.94-1.58 (m, 4H).

Workup

  1. customquenched with water
  2. extractionextracted with 2×30 mL of ethyl acetate
  3. concentrationThe combined organic layers were concentrated in vacuo
  4. customThe crude product (˜50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU))
  5. waitmobile phase, water with 0.05% TFA and CH3CN (26.0% CH3CN up to 42.0% in 7 min
  6. waitup to 100.0% in 2 min
  7. waitdown to 26.0% in 1 min)
  8. additionThe fractions containing pure compound

Sources & evidence

ORD record
ord-810ed8e0a727407e98b74dd9245dd459
Source dataset
uspto-grants-2014_10
Patent number
US08871790B2

Reaction notes

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