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

反応式

HRID 14120 の反応式
[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]

参加物

8

反応物 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

生成物 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

試薬・触媒・溶媒 3

HCID 8857Ethyl Acetate溶媒HCID 168937Lithium hydroxide, monohydrate溶媒HCID 21892291Methanol tetrahydrofuran water溶媒

実験手順

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]+.

後処理

  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)

出典と根拠

ORDレコード
ord-c3a1a4b0bffa4c1f9d8929f8582124ab
出典データセット
uspto-grants-2010_06
特許番号
US07727997B2

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