Hydrochloric Acid → Efipladib

HRID 730951

反応式

HRID 730951 の反応式
[NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:25])=[CH:8][CH:7]=2.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.N1C=CC=CC=1.[Cl:60][C:61]1[CH:62]=[C:63]([CH2:68][S:69](Cl)(=[O:71])=[O:70])[CH:64]=[CH:65][C:66]=1[Cl:67].Cl>ClCCl.CCCCCCC.C1(C)C=CC=CC=1.O>[CH:26]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:25])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:69]([CH2:68][C:63]1[CH:64]=[CH:65][C:66]([Cl:67])=[C:61]([Cl:60])[CH:62]=1)(=[O:71])=[O:70])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1

参加物

10

反応物 5

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 65279N,N-Bis(trimethylsilyl)trifluoroacetamideHCID 2794622(3,4-Dichlorophenyl)methanesulfonyl chlorideHCID 180085064-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoic acid

生成物 1

HCID 9853499Efipladib収率 72%

試薬・触媒・溶媒 4

HCID 962Water溶媒HCID 1140Toluene溶媒HCID 6344Dichloromethane溶媒2 回HCID 8900Heptane溶媒

反応条件

温度
35 °C

実験手順

To a suspension of 4-{3-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid (125.0 g, 0.239 mol) in dichloromethane (1.25 L) at ambient temperature, bis(trimethylsilyl)trifluoroacetamide (89.2 g, 0.347 mol) was added. After refluxing for 0.5 hours, the reaction mixture was cooled to 35° C. To the reaction mixture solution, pyridine (49.1 g, 0.621 mol) and a solution of (3,4-Dichloro-phenyl)-methanesulfonyl chloride (68.2 g, 0.263 mol) in dichloromethane (200 mL) were added successively. The reaction mixture was refluxed for 0.5 h and then cooled to room temperature. Water (1.25 L) and conc.HCl (61.6 g) were added to the reaction mixture successively. The organic layer was washed with water (600 mL×2) and concentrated. The concentrate was dissolved in 2-propanol (710 mL) added to cold water (2.45 L) and the crude product (173.0 g, yield 97%, HPLC 78%, SLI 11%) was collected after filtration. Pure 4-(3-{1-Benzhydryl-5-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid (WAY-195902, 125.0 g, yield 72%, HPLC 98%, SLI 033%) was obtained by successive treatment of the crude product with a mixture of toluene and heptane followed by a mixture of ethyl acetate and heptane. 1H NMR (DMSO−d6): δ12.80 (br.s, 1H), 7.89 (d, 2H, J=2 Hz), 7.59 (d, 1H, J=1.5 Hz), 7.53 (d,1H, J=6 Hz), 7.48 (d, 1H, J=1.5 Hz), 7.38 (m, 9H), 7.20 (m, 5H), 6.77 (dd, 1H, J=6.9 & 1.5 Hz), 6.46 (d, 1H, J=6.9 Hz), 4.36 (s, 2H), 3.18 (m,2H), 2.96 (m,2H), 2.76 (m, 4H), 1.90(m, 2H).

後処理

  1. temperatureAfter refluxing for 0.5 hours
  2. temperatureThe reaction mixture was refluxed for 0.5 h
  3. temperaturecooled to room temperature
  4. washThe organic layer was washed with water (600 mL×2)
  5. concentrationconcentrated
  6. dissolutionThe concentrate was dissolved in 2-propanol (710 mL)
  7. additionadded to cold water (2.45 L)
  8. customthe crude product (173.0 g, yield 97%, HPLC 78%, SLI 11%) was collected
  9. filtrationafter filtration

出典と根拠

ORDレコード
ord-d0d6026de6c74510aae29298d31220d0
出典データセット
uspto-grants-2009_09
特許番号
US07582771B2

関連ノート

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