Hydrochloric Acid → Efipladib

HRID 730951

Reaction equation

HRID 730951 reaction equation
[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

Participants

10

Reactant 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

Product 1

HCID 9853499EfipladibYield 72%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent2×HCID 8900HeptaneSolvent

Conditions

Temperature
35 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-d0d6026de6c74510aae29298d31220d0
Source dataset
uspto-grants-2009_09
Patent number
US07582771B2

Linked notes

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