Trifluoroacetic acid → tert-butyl ((6-(4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-hydroxypropyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)methyl)carbamate

HRID 1520534노트

반응식

HRID 1520534 반응식
Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[S:8][C:5]2=[N:6][CH:7]=1.[Cl:20][CH:21]([Cl:40])[C:22]([NH:24][C@H:25]([CH2:38][F:39])[C@H:26]([OH:37])[C:27]1[CH:32]=[CH:31][C:30]([Sn](C)(C)C)=[CH:29][CH:28]=1)=[O:23].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(NC(=O)[O-])(C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O.O.C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:20][CH:21]([Cl:40])[C:22]([NH:24][C@H:25]([CH2:38][F:39])[C@@H:26]([C:27]1[CH:28]=[CH:29][C:30]([C:2]2[CH:3]=[C:4]3[N:10]=[C:9]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[S:8][C:5]3=[N:6][CH:7]=2)=[CH:31][CH:32]=1)[OH:37])=[O:23]

참가 물질

10

반응물 5

HCID 6422Trifluoroacetic acidHCID 521585Tris(furan-2-yl)phosphaneHCID 21252905Tert-butylcarbamateHCID 866953832,2-Dichloro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)-ethyl]-acetamideHCID 86695489Tert-butyl ((6-bromothiazolo[5,4-b]pyridin-2-yl)methyl)carbamate

생성물 1

HCID 86695488tert-butyl ((6-(4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-hydroxypropyl)phenyl)thiazolo[5,4-b]pyridin-2-yl)methyl)carbamate수율 16.4%

시약·촉매·용매 4

HCID 962Water용매HCID 1140Toluene용매HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매

반응 조건

온도
65 °C

실험 절차

A mixture of tert-butyl ((6-bromothiazolo[5,4-b]pyridin-2-yl)methyl)carbamate (156 mg, 0.45 mmol), 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)-propan-2-yl)acetamide (200 mg, 0.45 mmol) and tris(2-furyl)phosphine (21 mg, 0.090 mmol) Tris(dibenzylideneacetone)dipalladium(0) (41 mg, 0.045 mmol) in dimethylformamide (2.5 mL) is heated at 65° C. for 3 hours under nitrogen. The mixture is then cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). Extracts are dried over Na2SO4 and concentrated to get crude title compound. m/z (Cl) M+1 543. To a solution of crude tert-butylcarbamate (200 mg, 0.452 mmol) in DCM (3 mL) is added trifluoroacetic acid (0.5 mL) and stirred at room temperature for 3 hours. Reaction is diluted with toluene (10 mL), concentrated under vacuum, basified with saturated aq NaHCO3 and extracted using ethyl acetate (3×10 mL). Extracts are dried over Na2SO4, concentrated and crude compound adsorbed on celite and purified on silica gel column using 0 to 20% methanol in ethyl acetate to give the title compound (40 mg). 1HNMR (DMSO-d6): 4.17 (m, 2H). 4.27 (m, 1.5H), 4.43 (m, 0.5H), 4.59 (m, 0.5H), 4.70 (m, 0.5H), 4.93 (m, 1H), 6.01 (m, 1H), 6.54 (1H), 7.50 (d, 2H), 7.80 (d, 2H), 8.51 (m, 1H), 8.64 (d, 1H), 8.87 (d, 1H), m/z (Cl) M+H 443.

후처리

  1. temperatureThe mixture is then cooled
  2. extractionextracted with ethyl acetate (3×10 mL)
  3. dry with materialExtracts are dried over Na2SO4
  4. concentrationconcentrated
  5. customto get crude title compound
  6. customReaction
  7. concentrationconcentrated under vacuum
  8. extractionextracted
  9. dry with materialExtracts are dried over Na2SO4
  10. concentrationconcentrated
  11. custompurified on silica gel column

출처 및 근거

ORD 기록
ord-44bc91aeae56481685d35ad803acafdc
출처 데이터셋
uspto-grants-2015_07
특허 번호
US09073894B2

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