Hydrochloric Acid → HCID 67682288、化合物

HRID 1751592ノート

反応式

HRID 1751592 の反応式
[F:1][C:2]1([F:59])[C:14]2[CH:13]=[C:12]([C:15]3[NH:19][C:18]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4C(OC(C)(C)C)=O)=[N:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([C:32]1[CH:33]=[CH:34][C:35]3[N:39]=[C:38]([C@@H:40]4[C@@H:45]5[CH2:46][C@@H:42]([CH2:43][CH2:44]5)[N:41]4[C:47](=[O:57])[C@@H](NC(OC)=O)C(C)C)[NH:37][C:36]=3[CH:58]=1)=[CH:6][CH:7]=2.Cl.O1C[CH2:65][O:64][CH2:63]C1.[CH3:67][O:68][C:69]([NH:71][C@H:72]([C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[C:73]([OH:75])=O)=[O:70].CCOC([C:87](C#N)=[N:88]OC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N([CH:115]([CH3:117])[CH3:116])CC)(C)C.C[OH:119]>>[CH3:65][O:64][C:63]([NH:88][C@@H:87]([CH:115]([CH3:116])[CH3:117])[C:47]([N:41]1[C@H:40]([C:38]2[NH:37][C:36]3[CH:58]=[C:32]([C:5]4[CH:4]=[C:3]5[C:8]([C:9]6[CH:10]=[CH:11][C:12]([C:15]7[NH:19][C:18]([C@@H:20]8[CH2:24][CH2:23][CH2:22][N:21]8[C:73](=[O:75])[C@H:72]([NH:71][C:69](=[O:70])[O:68][CH3:67])[C:76]8[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=8)=[N:17][CH:16]=7)=[CH:13][C:14]=6[C:2]5([F:59])[F:1])=[CH:7][CH:6]=4)[CH:33]=[CH:34][C:35]=3[N:39]=2)[C@@H:45]2[CH2:46][C@H:42]1[CH2:43][CH2:44]2)=[O:57])=[O:119]

参加物

8

反応物 7

HCID 313Hydrochloric AcidHCID 887MethanolHCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 67682549HCID 67682549、化合物HCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

生成物 1

HCID 67682288HCID 67682288、化合物収率 24%

反応条件

温度
0 °C

実験手順

A solution of (S)-tert-butyl 2-(5-(9,9-difluoro-7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (106 mg, 0.13 mmol), methanol (1.5 mL), and 4M HCl in dioxane (1.5 mL, 6 mmol) was stirred at room temperature. The reaction was thoroughly concentrated after thirty minutes. The resulting residue was dissolved in a 4:1 dichloromethane:dimethylformamide solution (1.3 mL). To this solution was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (28 mg, 0.13 mmol) and COMU (56 mg, 0.13 mmol) and the reaction was cooled to 0° C. Diisopropylethylamine (0.092 mL, 0.53 mmol) was added and the reaction was stirred at 0° C. for twenty minutes. The reaction was quenched by the addition of formic acid (0.05 mL) and thoroughly concentrated. The resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 60% ACN/H2O+0.1% TFA) to yield methyl (R)-2-((S)-2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (28 mg, 24%). LCMS-ESI+: calculated for C50H50F2N8O6: 897.0; observed [M+1]+: 898.1.

後処理

  1. concentrationThe reaction was thoroughly concentrated after thirty minutes
  2. dissolutionThe resulting residue was dissolved in a 4:1 dichloromethane
  3. customThe reaction was quenched by the addition of formic acid (0.05 mL)
  4. concentrationthoroughly concentrated
  5. customThe resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 60% ACN/H2O+0.1% TFA)

出典と根拠

ORDレコード
ord-7ade1a5c5c244eeaba637272cf298a1d
出典データセット
uspto-grants-2015_10
特許番号
US09156823B2

反応ノート

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