1,2-Dichloroethane → N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N3,N3-dipropyl-5-(1,3-thiazol-2-yl)isophthalamide

HRID 349079Notes

Reaction equation

HRID 349079 reaction equation
[CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].Cl.Cl.[NH2:26][C@@H:27]([CH2:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[CH:43]=1)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C)C=O.O>[F:48][C:46]1[CH:47]=[C:42]([CH:43]=[C:44]([F:49])[CH:45]=1)[CH2:41][C@H:27]([NH:26][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=1

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 210857833-[(Dipropylamino)carbonyl]-5-(1,3-thiazol-2-yl)benzoic AcidHCID 57487281(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride

Product 1

HCID 58802355N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N3,N3-dipropyl-5-(1,3-thiazol-2-yl)isophthalamideYield 10.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A solution of 3-[(dipropylamino)carbonyl]-5-(1,3-thiazol-2-yl)benzoic acid (156 mg, 0.47 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (191 mg, 0.47 mmol), HOBt (64 mg, 0.47 mmol), and N-methylmorpholine (200 μL, 1.5 mmol) was stirred in dimethylformamide (2 mL) for 15 min. EDC (145 mg, 0.84 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}-N3,N3-dipropyl-5-(1,3-thiazol-2-yl)isophthalamide (33 mg): 1H NMR (500 MHz, CDCl3) δ 8.40 (br s, 1H, —NH), 8.15 (br s, 1H), 7.94 (br s, 1H), 7.80 (d, J=3 Hz, 1H), 7.51 (br s, 1H), 7.34 (d, J=3 Hz, 1H), 7.27–7.24 (m, 1H), 7.21–7.18 (m, 2H), 7.11–7.10 (m, 1H), 7.00 (br s, 1H), 6.62–6.58 (m, 1H), 4.23 (d, J=5 Hz, 1H), 3.91–3.85 (m, 3H), 3.57 (br s, 2H), 3.31 (br s, 2H), 3.05 (d, J=5 Hz, 4H), 2.83 (d, J=6 Hz, 2H), 2.64 (q, J=8 Hz, 2H), 1.75 (br s, 2H), 1.44 (t, J=7 Hz, 2H), 1.22 (t, J=8 Hz, 3H) 1.04 (t, J=7 Hz, 3H), 0.65 (t, J=7 Hz, 3H); ESI MS m/z 649 [M+H]+;

Workup

  1. extractionextracted with ethyl acetate (3×25 mL)
  2. washThe organic layer was 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-65ea5a5a65f2460f9b2bcfc6604576a3
Source dataset
uspto-grants-2007_02
Patent number
US07176242B2

Reaction notes

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