Diisopropylethylamine → 3-{[Butyl(methyl)amino]methyl}-N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-5-(1,3-oxazol-2-yl)benzamide Dihydrochloride

HRID 14120

Reaktionsgleichung

Reaktionsgleichung von HRID 14120
[CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[CH:17]=1)[C:11]([O:13]C)=O)[CH3:6])[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:56].Cl.[NH2:58][C@@H:59]([CH2:75][C:76]1[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=1)[C@H:60]([OH:74])[CH2:61][NH:62][C:63]1([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]#[CH:73])[CH:67]=2)[CH2:65][CH2:64]1>O1CCCC1.CO.O.O.[OH-].[Li+].C(OCC)(=O)C>[ClH:56].[ClH:56].[CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[CH:17]=1)[C:11]([NH:58][C@@H:59]([CH2:75][C:76]1[CH:77]=[C:78]([F:83])[CH:79]=[C:80]([F:82])[CH:81]=1)[C@H:60]([OH:74])[CH2:61][NH:62][C:63]1([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]#[CH:73])[CH:67]=2)[CH2:65][CH2:64]1)=[O:13])[CH3:6])[CH2:2][CH2:3][CH3:4]

Komponenten

8

Edukt 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 21086166Methyl 3-{[butyl(methyl)amino]methyl}-5-(1,3-oxazol-2-yl)benzoateHCID 57487320(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}butan-2-ol dihydrochloride

Produkt 1

HCID 865941973-{[Butyl(methyl)amino]methyl}-N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-5-(1,3-oxazol-2-yl)benzamide Dihydrochloride

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 8857Ethyl AcetateLösungsmittelHCID 168937Lithium hydroxide, monohydrateLösungsmittelHCID 21892291Methanol tetrahydrofuran waterLösungsmittel

Versuchsvorschrift

Methyl 3-{[butyl(methyl)amino]methyl}-5-(1,3-oxazol-2-yl)benzoate (30 mg, 0.1 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (10 mg, 0.2 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (1 mL), and diisopropylethylamine (70 μL, 0.4 mmol), HATU (57 mg, 0.15 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}butan-2-ol dihydrochloride (203 mg, 0.5 mmol) are added. The reaction stirred at room temperature 2 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9-10% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (1 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 627.3 [M+H]+.

Aufarbeitung

  1. additionis added (10 mg, 0.2 mmol)
  2. concentrationThe solution is concentrated under reduced pressure
  3. dissolutionThe residue is redissolved in DMF (1 mL)
  4. stirringThe reaction stirred at room temperature 2 h
  5. washwashed with water, saturated sodium bicarbonate, brine
  6. dry with materialdried (sodium sulfate)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customPurification by flash column chromatography (silica, 9-10% methanol/methylene chloride)

Quellen und Nachweise

ORD-Eintrag
ord-c3a1a4b0bffa4c1f9d8929f8582124ab
Quelldatensatz
uspto-grants-2010_06
Patentnummer
US07727997B2

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