1-Hydroxybenzotriazole → 4-Butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide

HRID 14220Notes

Reaction equation

HRID 14220 reaction equation
[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].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.Cl.Cl.[NH2:63][C@@H:64]([CH2:78][C:79]1[CH:84]=[C:83]([F:85])[CH:82]=[C:81]([F:86])[CH:80]=1)[C@H:65]([OH:77])[CH2:66][NH:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][CH3:76])[CH:70]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([NH:63][C@@H:64]([CH2:78][C:79]3[CH:80]=[C:81]([F:86])[CH:82]=[C:83]([F:85])[CH:84]=3)[C@H:65]([OH:77])[CH2:66][NH:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][CH3:76])[CH:70]=3)=[O:17])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]

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 210859294-Butyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acidHCID 57487281(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride

Product 1

HCID 575126124-Butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamideYield 17.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A solution of 4-Butyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (43 mg), HATU (104 mg), HOBt (37 mg), and diisopropylethylamine (47 μL) was stirred in methylene chloride (1.0 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (62 mg) and diisopropylethylamine (47 μL) in methylene chloride (1.0 mL) was added and the reaction mixture was stirred overnight. The mixture was diluted with methylene chloride, washed with 1 N hydrochloric acid (15 mL), saturated sodium bicarbonate (15 mL), and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided 15 mg of the title compound: APCI MS m/z 552 [M+H]+.

Workup

  1. washwashed with 1 N hydrochloric acid (15 mL), saturated sodium bicarbonate (15 mL), and brine
  2. dry with materialdried (magnesium sulfate)
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customPurification by flash column chromatography (silica, 1:9 methanol/chloroform)

Sources & evidence

ORD record
ord-5d6a6c6cca1646529a2c270e412a85e8
Source dataset
uspto-grants-2010_06
Patent number
US07727997B2

Reaction notes

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