Hydrochloric Acid → n-[(1S)-(2s)-(3-fluorophenyl)-2-{[1-(4-fluorophenyl)-1h-indazole-5-yl]oxy}-1-(methoxymethyl)ethyl]-2-methoxyacetamide

HRID 1098893

Reaktionsgleichung

Reaktionsgleichung von HRID 1098893
[NH:1]([C:9]([O:11]C(C)(C)C)=O)[C@H:2]([C:6]([OH:8])=O)[CH2:3][O:4][CH3:5].Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[C:27](=[CH:28][C:29](I)=[CH:30][CH:31]=3)[CH:26]=[N:25]2)=[CH:20][CH:19]=1.C(N([CH2:39][CH3:40])CC)C.[CH3:41][O:42][CH2:43]C(Cl)=O>ClCCl>[C:27]1([CH2:26][CH2:2][NH2:1])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[F:17][C:18]1[CH:19]=[C:20]([C@H:6]([O:8][C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[N:25]=[CH:26]3)[C@@H:2]([NH:1][C:9](=[O:11])[CH2:43][O:42][CH3:41])[CH2:3][O:4][CH3:5])[CH:21]=[CH:39][CH:40]=1

Komponenten

8

Edukt 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 96623Methoxyacetyl chlorideHCID 7016354(2S)-2-(((tert-butoxy)carbonyl)amino)-3-methoxypropanoic acidHCID 592511281-(4-fluorophenyl)-5-iodo-1H-indazole

Produkt 2

HCID 1001PhenethylamineHCID 66812425n-[(1S)-(2s)-(3-fluorophenyl)-2-{[1-(4-fluorophenyl)-1h-indazole-5-yl]oxy}-1-(methoxymethyl)ethyl]-2-methoxyacetamideAusbeute 7,6 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel2×

Versuchsvorschrift

(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-(methoxymethyl])benzeneethanamine is synthesized in analogy to the sequence described in example 1: commercially available Boc-Ser(Me)-OH is transformed into its Weinreb-amide. Reduction to the aldehyde with LiAlH, followed by reaction with 3-fluorophenylgrignard, cleavage of the protecting group, liberation of the amine from the hydrochloride and etherification with 1-(4-fluorophenyl)-5-iodo-1H-indazole. This amine (66.4 mg, 0.16 mmol) is dissolved in 7 mL of dichloromethane. Triethylamine (0.054 mL, 0.39 mmol) and 0.018 mL (0.19 mmol) 2-methoxyacetylchloride are added. The reaction mixture is stirred for four h at r.t. and then diluted with dichloromethane, washed with water and brine and dried over Na2SO4. After filtration the solvent is evaporated and the residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane). The mixture of stereoisomers is separated by HPLC (Chiralpak AD-H 5μ, eluents: hexane/ethanol) providing 3 mg (3.8%) of the title compound and 6 mg (7.6%) of the stereoisomer N-[(1S)-(2S)-(3-fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-(methoxymethyl)ethyl]-2-methoxyacetamide.

Aufarbeitung

  1. washwashed with water and brine
  2. dry with materialdried over Na2SO4
  3. filtrationAfter filtration the solvent
  4. customis evaporated
  5. customthe residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane)
  6. additionThe mixture of stereoisomers
  7. customis separated by HPLC (Chiralpak AD-H 5μ, eluents: hexane/ethanol)

Quellen und Nachweise

ORD-Eintrag
ord-b2884cdad58149d987dc93dd2479d0fe
Quelldatensatz
uspto-grants-2012_03
Patentnummer
US08143290B2

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