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

HRID 13131

반응식

HRID 13131 반응식
[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].[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:38]3[C:33](=[CH:34][C:35](I)=[CH:36][CH:37]=3)[CH:32]=[N:31]2)=[CH:26][CH:25]=1.C(N([CH2:45][CH3:46])CC)C.[CH3:47][O:48][CH2:49]C(Cl)=O>ClCCl>[C:33]1([CH2:32][CH2:2][NH2:1])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1.[F:23][C:24]1[CH:25]=[C:26]([C@H:6]([O:8][C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:31]=[CH:32]3)[C@@H:2]([NH:1][C:9](=[O:11])[CH2:49][O:48][CH3:47])[CH2:3][O:4][CH3:5])[CH:27]=[CH:45][CH:46]=1

참가 물질

9

반응물 6

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 96623Methoxyacetyl chlorideHCID 7016354(2S)-2-(((tert-butoxy)carbonyl)amino)-3-methoxypropanoic acidHCID 21226445Aluminium lithium hydrideHCID 592511281-(4-fluorophenyl)-5-iodo-1H-indazole

생성물 2

HCID 1001PhenethylamineHCID 66812425n-[(1S)-(2s)-(3-fluorophenyl)-2-{[1-(4-fluorophenyl)-1h-indazole-5-yl]oxy}-1-(methoxymethyl)ethyl]-2-methoxyacetamide수율 7.6%

시약·촉매·용매 1

HCID 6344Dichloromethane용매2회

실험 절차

(αS)-3-Fluoro-γ-[[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 LiAlH4, 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.

후처리

  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)

출처 및 근거

ORD 기록
ord-0e3d8a8b3aff4642a9d7b0c7e64fbc14
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07728030B2

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