Triethylamine → 4-[3-(4-Dimethylamino-benzyl)-ureido]-butyric acid benzyl ester

HRID 404197Notes

Reaction equation

HRID 404197 reaction equation
C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][NH2:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.Cl.Cl.[CH3:47][N:48]([CH3:57])[C:49]1[CH:56]=[CH:55][C:52]([CH2:53][NH2:54])=[CH:51][CH:50]=1>ClCCl.[Cl-].[Na+].O>[CH2:12]([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][NH:24][C:30]([NH:54][CH2:53][C:52]1[CH:55]=[CH:56][C:49]([N:48]([CH3:57])[CH3:47])=[CH:50][CH:51]=1)=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1

Participants

7

Reactant 4

HCID 8471Triethylamine2×HCID 94429TriphosgeneHCID 27346334-(aminomethyl)-N,N-dimethylaniline dihydrochlorideHCID 200718004-Methylbenzene-1-sulfonic acid; benzyl 4-aminobutanoate

Product 1

HCID 670068264-[3-(4-Dimethylamino-benzyl)-ureido]-butyric acid benzyl esterYield 278.4%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

To a vigorous stirred suspension of 4-amino-butyric acid benzyl ester toluene-4-sulfonic acid (0330 g, 2.00 mmol) and triphosgene (0.200 g, 0.667 mmol) in dichloromethane (40 mL) at −78° C. under nitrogen atmosphere, was added triethylamine (1.0 mL, 7.188 mmol, in 10 mL dichloromethane) dropwise via an additional funnel over a period of 2 hours. The cooling bath was removed and the resulting reaction was allowed to stir at room temperature for 1 hour, after which time 4-dimethylaminobenzylamine dihydrochloride (0.446 g, 2.00 mmol) was added to the reaction mixture, followed by triethylamine (0.67 mL, 4.8 mmol). The resulting reaction was allowed to stir for about 18 h, then the reaction mixture was diluted with brine (20 mL), transferred to a separatory funnel and the aqueous layer was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide a crude residue which was purified by flash column chromatography (silica gel 60, CH2Cl2/EtOAc=4:1 to 2:1) to afford 4-[3(4-Dimethylamino-benzyl)-ureido]-butyric acid benzyl ester (0.686 g, 93% yield). 1H NMR (300 MHz, CDCl3) δ (ppm) 7.31 (m, 5H), 7.09 (d, J=9.0 Hz, 2H), 6.63 (d, J=9.0 Hz, 2H), 5.20 (t, J=5.4 Hz, 1H), 5.09 (t, J=5.4 Hz, 1H), 5.05 (s, 2H), 4.14 (d, J=5.7 Hz, 2H), 3.09 (dt, J=6.6, 6.3 Hz, 2H), 2.86 (s, 6H), 2.32 (t, J=7.5 Hz, 2H), 1.73 (m, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm) 173.3, 158.5, 149.8, 135.8, 128.5, 128.15, 128.09, 127.0, 112.6, 66.2, 43.9, 40.7, 39.5, 31.5, 25.4.

Workup

  1. customThe cooling bath was removed
  2. customthe resulting reaction
  3. customThe resulting reaction
  4. stirringto stir for about 18 h
  5. customtransferred to a separatory funnel
  6. extractionthe aqueous layer was extracted with dichloromethane
  7. dry with materialThe organic layer was dried over sodium sulfate
  8. concentrationconcentrated in vacuo
  9. customto provide a crude residue which
  10. customwas purified by flash column chromatography (silica gel 60, CH2Cl2/EtOAc=4:1 to 2:1)

Sources & evidence

ORD record
ord-612e39195ba44b3da472b1a8d735260c
Source dataset
uspto-grants-2014_06
Patent number
US08748463B2

Reaction notes

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