1-Hydroxybenzotriazole → N1-{(1S,2R)-1-(3,5-Difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(5-methyl-1,2,4-oxadiazol-3-yl)-N3,N3-dipropylisophthalamide Hydrochloride

HRID 14061

Reaction equation

HRID 14061 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[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[ClH:68].Cl.[NH2:70][C@@H:71]([CH2:85][C:86]1[CH:91]=[C:90]([F:92])[CH:89]=[C:88]([F:93])[CH:87]=1)[C@H:72]([OH:84])[CH2:73][NH:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[C:78]([CH2:82][CH3:83])[CH:77]=1>C(Cl)Cl>[ClH:68].[F:92][C:90]1[CH:91]=[C:86]([CH:87]=[C:88]([F:93])[CH:89]=1)[CH2:85][C@H:71]([NH:70][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:22][CH2:23][CH3:24])=[O:6])[CH:8]=1)[C@H:72]([OH:84])[CH2:73][NH:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[C:78]([CH2:82][CH3:83])[CH:77]=1

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531Diisopropylethylamine2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 210857883-[(Dipropylamino)carbonyl]-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic AcidHCID 57487281(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride

Product 1

HCID 68607417N1-{(1S,2R)-1-(3,5-Difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(5-methyl-1,2,4-oxadiazol-3-yl)-N3,N3-dipropylisophthalamide Hydrochloride

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A solution of 3-[(dipropylamino)carbonyl]-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (209 mg, 0.63 mmol), HATU (359 mg, 0.95 mmol), HOBt (128 mg, 0.95 mmol), and diisopropylethylamine (165 μL, 0.95 mmol) is stirred in methylene chloride (2.0 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method in Example SP-272 (257 mg, 0.63 mmol) and diisopropylethylamine (165 μL, 0.95 mmol) in methylene chloride (2.0 mL) is added and the reaction mixture is stirred overnight. The reaction mixture is diluted with methylene chloride, washed with 1 N hydrochloric acid (25 mL), saturated sodium bicarbonate (25 mL), and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provides the title compound as the free base. The solid is dissolved in methanol (1 mL), and treated with hydrochloric acid (0.3 mL of a 1.0 M solution in diethyl ether, 0.3 mmol). The resulting precipitate is collected by filtration to provide the title compound. APCI MS m/z 648.4 [M+H]+.

Workup

  1. additionis added
  2. washwashed with 1 N hydrochloric acid (25 mL), saturated sodium bicarbonate (25 mL), and brine
  3. dry with materialdried (magnesium sulfate)
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customPurification by flash column chromatography (silica, 1:9 methanol/chloroform)

Sources & evidence

ORD record
ord-850f8369adcb4fd8b5fa402985e7cbc3
Source dataset
uspto-grants-2010_06
Patent number
US07727997B2

Linked notes

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