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

HRID 14114

反応式

HRID 14114 の反応式
[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:14])[CH:11]=1)[C:5]([O:7]C)=O.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:52].Cl.[NH2:54][C@@:55](C)([CH2:71][C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=1)[C@H:56]([OH:70])[CH2:57][NH:58][C:59]1([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]#[CH:69])[CH:63]=2)[CH2:61][CH2:60]1>O1CCCC1.CO.O.O.[OH-].[Li+]>[ClH:52].[ClH:52].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:14])[CH:11]=1)[C:5]([NH:54][C@@H:55]([CH2:71][C:72]1[CH:73]=[C:74]([F:79])[CH:75]=[C:76]([F:78])[CH:77]=1)[C@H:56]([OH:70])[CH2:57][NH:58][C:59]1([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]#[CH:69])[CH:63]=2)[CH2:61][CH2:60]1)=[O:7]

参加物

7

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 21086161Methyl 3-bromo-5-{[butyl(methyl)amino]methyl}benzoateHCID 57487326(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}-3-methylbutan-2-ol dihydrochloride

生成物 1

HCID 865941963-Bromo-5-{[butyl(methyl)amino]methyl}-N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)benzamide Dihydrochloride

試薬・触媒・溶媒 2

HCID 168937Lithium hydroxide, monohydrate溶媒HCID 21892291Methanol tetrahydrofuran water溶媒

実験手順

Methyl 3-bromo-5-{[butyl(methyl)amino]methyl}benzoate (113 mg, 0.36 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (30 mg, 0.72 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (5 mL), and diisopropylethylamine (250 μL, 1.44 mmol), HATU (170 mg, 0.45 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]amino}-3-methylbutan-2-ol dihydrochloride prepared as in Example SP-264 (170 mg, 0.4 mmol) are added. The reaction stirred at room temperature 16 h. Purification by flash column chromatography (silica, 8% 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 638.2 [M+H]+.

後処理

  1. additionis added (30 mg, 0.72 mmol)
  2. concentrationThe solution is concentrated under reduced pressure
  3. dissolutionThe residue is redissolved in DMF (5 mL)
  4. additionare added
  5. stirringThe reaction stirred at room temperature 16 h
  6. customPurification by flash column chromatography (silica, 8% methanol/methylene chloride)

出典と根拠

ORDレコード
ord-8ebc952d4656474bbdce3b4d3fe75770
出典データセット
uspto-grants-2010_06
特許番号
US07727997B2

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