반응 #41409

반응 방정식

Triethylamine

2-methoxyacetylchloride

LiAlH4

hydrochloride

1-(4-fluorophenyl)-5-iodo-1H-indazole

Boc-Ser(Me)-OH

→

benzeneethanamine

N-[(1S)-(2S)-(3-fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-(methoxymethyl)ethyl]-2-methoxyacetamide

수율 7.6%

용매

dichloromethane

dichloromethane

반응 조건

후처리

1. 1
   세척washed with water and brine
2. 2
   건조dried over Na2SO4
3. 3
   여과After filtration the solvent
4. 4
   기타is evaporated
5. 5
   기타the residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane)
6. 6
   workup.ADDITIONThe mixture of stereoisomers
7. 7
   기타is separated by HPLC (Chiralpak AD-H 5μ, eluents: hexane/ethanol)

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.

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