(1S)-(+)-Camphor-10-sulphonic acid → 4-(3-Dimethylaminoazetidin-1-yl)piperidine-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylthioureido)phenoxy]pyridin-2-yl}amide

HRID 492964노트

반응식

HRID 492964 반응식
[NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:47]1([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.CCCCCC.C(OCC)C.C(OCC)(=O)C>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:58])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:23][CH:24]([N:26]([CH3:27])[CH3:28])[CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1

참가 물질

10

반응물 4

HCID 218580(1S)-(+)-Camphor-10-sulphonic acidHCID 516892Sodium BicarbonateHCID 12454157Phenylacetyl isothiocyanateHCID 576776534-(3-Dimethylaminoazetidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide

생성물 1

HCID 576773344-(3-Dimethylaminoazetidin-1-yl)piperidine-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylthioureido)phenoxy]pyridin-2-yl}amide수율 25.7%

시약·촉매·용매 5

HCID 702Ethanol용매HCID 1140Toluene용매HCID 3283Diethyl Ether용매HCID 8058Hexane용매HCID 8857Ethyl Acetate용매

실험 절차

To a solution of 4-(3-dimethylaminoazetidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (156 mg) in ethanol (5.0 ml) was added (1S)-(+)-10-camphorsulfonic acid (152 mg), followed by stirring at room temperature for 15 min. A solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 4.37 ml) was added to the reaction mixture, followed by stirring at room temperature for 2 hrs. Ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml) were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing a crude product were concentrated to give a residue, to which diethyl ether (5 ml) and hexane (5 ml) were added to give a precipitate. The precipitate was suspended in the solvent. Then the precipitate was filtered off, washed with hexane, and dried under aeration to provide the titled compound (56.6 mg, 25.7%) as pale yellow powder.

후처리

  1. stirringby stirring at room temperature for 2 hrs
  2. customthe organic layer was separated
  3. extractionThe aqueous layer was extracted with ethyl acetate
  4. washThe combined organic layer was washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationThe organic layer was concentrated
  7. customto give a residue, which
  8. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent
  9. additionFractions containing a crude product
  10. concentrationwere concentrated
  11. customto give a residue
  12. customto give a precipitate
  13. filtrationThen the precipitate was filtered off
  14. washwashed with hexane
  15. customdried under aeration

출처 및 근거

ORD 기록
ord-ff494c2f410940c6b55f850f2fbc3e20
출처 데이터셋
uspto-grants-2009_05
특허 번호
US07531532B2

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