1-Hydroxybenzotriazole → HCID 178432709, compound

HRID 1487821Notes

Reaction equation

HRID 1487821 reaction equation
[CH3:1][C:2]1[NH:3][C:4]([C:8]2[C:9]([CH3:18])=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[C:5]([CH3:7])[N:6]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[NH:42]1[CH2:47][CH2:46][CH:45]([C:48]2[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][CH:49]=2)[CH2:44][CH2:43]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][C:2]1[NH:3][C:4]([C:8]2[C:9]([CH3:18])=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([N:42]2[CH2:47][CH2:46][CH:45]([C:48]3[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][CH:49]=3)[CH2:44][CH2:43]2)=[O:15])=[C:5]([CH3:7])[N:6]=1

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 193916184-(Piperidin-4-yl)benzonitrile--hydrogen chloride (1/1)2×HCID 178432712HCID 178432712, compound2×

Product 1

HCID 178432709HCID 178432709, compoundYield 50.4%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

A mixture of 5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 1.8, 280 mg, 1.15 mmol), EDC.HCl (330 mg, 1.72 mmol), 4-dimethylaminopyridine (420 mg, 3.44 mmol), and HOBT (180 mg, 1.33 mmol) in N,N-dimethylformamide (6 mL) was stirred at room temperature. After 5 min, 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 230 mg, 1.03 mmol) was added and the resulting solution was stirred at room temperature for 15 h, then quenched with ice water (20 mL). The aqueous was extracted with ethyl acetate (50 mL) and the combined organics was washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (22% CH3CN up to 37% in 7 min, up to 100% in 2 min, down to 22% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (214 mg, 50%). m/z (ES+) 413 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.68 (d, J=7.8 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.36 (br s, 1H), 7.27 & 7.16 (2 singlets, rotamers, Ar—H, 1H), ˜4.9-4.82 (m, 1H partially obscured by water peak), 3.72-3.55 (m, 1H), ˜3.35-3.20 (m, 1H partially overlapped with methanol solvent peak), 3.08-2.92 (m, 2H), 2.65 (s, 3H), 2.44 & 2.34 (2 singlets, rotamers, Ar—CH3, 3H), 2.29 (s, 3H), 2.22 (s, 3H), 2.10-1.96 (m, 1H), 1.93-1.53 (m, 3H).

Workup

  1. stirringthe resulting solution was stirred at room temperature for 15 h
  2. customquenched with ice water (20 mL)
  3. extractionThe aqueous was extracted with ethyl acetate (50 mL)
  4. washthe combined organics was washed with brine (2×50 mL)
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU))
  9. waitmobile phase, water with 0.05% TFA and CH3CN (22% CH3CN up to 37% in 7 min
  10. waitup to 100% in 2 min
  11. waitdown to 22% in 1 min)
  12. additionThe fractions containing pure compound

Sources & evidence

ORD record
ord-605d6c66828544e1b78fa841e9777f3b
Source dataset
uspto-grants-2016_08
Patent number
US09428502B2

Reaction notes

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