Hydrochloric Acid → Efipladib

HRID 730951

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HRID 730951 반응식
[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

참가 물질

10

반응물 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

생성물 1

HCID 9853499Efipladib수율 72%

시약·촉매·용매 4

HCID 962Water용매HCID 1140Toluene용매HCID 6344Dichloromethane용매2회HCID 8900Heptane용매

반응 조건

온도
35 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-d0d6026de6c74510aae29298d31220d0
출처 데이터셋
uspto-grants-2009_09
특허 번호
US07582771B2

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