1,2-Dichloroethane → N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(4-methyl-1,3-oxazol-2-yl)-N3,N3-dipropylisophthalamide

HRID 14287Notes

Reaction equation

HRID 14287 reaction equation
[CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[O:17][CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:6])[CH2:2][CH3:3].Cl.Cl.[NH2:27][C@@H:28]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[C@H:29]([OH:41])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[CH:34]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C)C=O.O>[F:50][C:45]1[CH:44]=[C:43]([CH:48]=[C:47]([F:49])[CH:46]=1)[CH2:42][C@H:28]([NH:27][C:10](=[O:11])[C:9]1[CH:13]=[C:14]([C:16]2[O:17][CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:22][CH2:23][CH3:24])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:29]([OH:41])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[CH:34]=1

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 210857873-[(Dipropylamino)carbonyl]-5-(4-methyl-1,3-oxazol-2-yl)benzoic acidHCID 57487281(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride

Product 1

HCID 58802778N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(4-methyl-1,3-oxazol-2-yl)-N3,N3-dipropylisophthalamideYield 26.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A solution of 3-[(dipropylamino)carbonyl]-5-(4-methyl-1,3-oxazol-2-yl)benzoic acid (77.5 mg, 0.23 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (96 mg, 0.23 mmol), HOBt (32 mg, 0.23 mmol), and N-methylmorpholine (83 μL, 0.75 mmol) was stirred in dimethylformamide (2 mL) for 15 min. EDC (73 mg, 0.42 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with water, and extracted with ethyl acetate (3×25 mL) The organic layer was washed with 1 N hydrochloric acid (25 mL), saturated sodium bicarbonate (25 mL), saturated sodium chloride, dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(4-methyl-1,3-oxazol-2-yl)-N3,N3-dipropylisophthalamide (40 mg): 1H NMR (300 MHz, CDCl3) δ 8.20 (br s, 1H, —NH), 8.17 (s, 1H), 8.05 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.24-7.08 (m, 5H), 7.02 (d, J=8 Hz, 2H), 6.61 (t, J=8 Hz, 1H), 4.27 (br s, 1H), 3.93 (d, J=4 Hz, 1H), 3.85 (s, 2H), 3.54 (br s, 2H), 3.43 (br s, 2H), 2.84 (d, J=5 Hz, 2H), 2.63 (q, J=8 Hz, 2H), 2.18 (s, 3H), 1.74 (t, J=5 Hz, 2H), 1.41 (d, J=7 Hz, 2H), 1.22 (t, J=8 Hz, 3H), 1.03 (t, J=7 Hz, 3H), 0.64 (t, J=7 Hz, 3H); ESI MS m/z 647 [M+H]+

Workup

  1. extractionextracted with ethyl acetate (3×25 mL) The organic layer
  2. washwas washed with 1 N hydrochloric acid (25 mL), saturated sodium bicarbonate (25 mL), saturated sodium chloride
  3. dry with materialdried (sodium sulfate)
  4. concentrationconcentrated under reduced pressure
  5. customPurification by flash column chromatography (silica, 1:9 methanol/chloroform)

Sources & evidence

ORD record
ord-84487bd89e1e4493b433a9e520730bcd
Source dataset
uspto-grants-2010_06
Patent number
US07727997B2

Reaction notes

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