1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 3-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid methyl ester

HRID 277188Notes

Reaction equation

HRID 277188 reaction equation
[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Br.[CH3:53][O:54][C:55](=[O:69])[CH2:56][CH2:57][C:58]1[O:62][N:61]=[C:60]([CH:63]([NH2:68])[CH2:64][CH:65]([CH3:67])[CH3:66])[CH:59]=1>C(Cl)Cl.O>[CH3:53][O:54][C:55](=[O:69])[CH2:56][CH2:57][C:58]1[O:62][N:61]=[C:60]([CH:63]([NH:68][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:21])=[O:20])=[CH:15][CH:14]=2)[CH2:64][CH:65]([CH3:67])[CH3:66])[CH:59]=1

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 66052544-((((2-Methylphenyl)amino)carbonyl)amino)benzeneacetic acidHCID 696929213-[3-(1-Amino-3-methyl-butyl)-isoxazol-5-yl]-propionic acid methyl ester hydrobromide

Product 1

HCID 186823683-[3-(3-Methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-isoxazol-5-yl]-propionic acid methyl esterYield 51.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent3×

Procedure

To a stirred solution of [4-(3-o-tolyl-ureido)-phenyl]-acetic acid (305 mg, 1.07 mmol), DIEA (1.3 ml), HOBT (120 mg, 0.89 mmol) and EDCI (170 mg, 0.89 mmol) in CH2Cl2 (8 ml) at room temperature was added a solution of 3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-propionic acid methyl ester hydrobromide (272 mg, 0.85 mmol) in CH2Cl2 (12 ml). After stirring for 16 h at room temperature the mixture was diluted with CH2Cl2 (20 ml) and poured into water. The layers were separated and the aqueous layer was extracted with CH2Cl2 (20 ml×3). The combined organics were dried over MgSO4; filtered; and concentrated under reduced pressure. The residue was purified by Flash 40 chromatography using a silica gel column and eluting with 65% EtOAc/hexane to give 220 mg of the title compound as a white amorphous solid. MP 153-4° C.; MS [+1]+507.2; 1H nmr (400 MHz, CDCl3) δ0.88 (d, J=6.4 Hz, 6H), 1.53-1.66 (m, 3H), 2.21 (s, 3H), 2.66 (t, J=7.6 Hz, 2H), 3.00 (t, J=7.6 Hz, 2H), 3.49 (s, 2H), 3.68 (s, 3H), 5.15 (dt, J=6.2 and 8.7 Hz, 1H), 5.85 (s, 1H), 6.11 (d, J=8.5 Hz, 1H), 6.65 (s, 1H), 7.00 (s, 1H), 7.05-7.24 (m, 7H), 7.53 (d, 1H); Anal. calcd. for C28H34N4O5: C (66.39), H (6.76), N (11.05). Found: C (66.29), H (7.11), N (11.11).

Workup

  1. customThe layers were separated
  2. extractionthe aqueous layer was extracted with CH2Cl2 (20 ml×3)
  3. dry with materialThe combined organics were dried over MgSO4
  4. filtrationfiltered
  5. concentrationand concentrated under reduced pressure
  6. customThe residue was purified by Flash 40 chromatography
  7. washeluting with 65% EtOAc/hexane

Sources & evidence

ORD record
ord-be398cdd3d1547efbb9e7a986b5d5a89
Source dataset
uspto-grants-2002_03
Patent number
US06355662B1

Reaction notes

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