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Lithium Chloride → 2,2-Difluoro-N-((1S,2R)-1-fluoromethyl-2-hydroxy-2-{4-[2-(methanesulfonylamino-methyl)-benzothiazol-5-yl]-phenyl}-ethyl)-acetamide

HRID 1487468
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HRID 1487468 반응식
Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:7][C:6]=2[CH:16]=1.[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20].[Cl-].[Li+]>CN1CCCC1=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:7][C:6]=3[CH:16]=2)=[CH:28][CH:29]=1)=[O:20]
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참가 물질

7

반응물 3

HCID 433294Lithium ChlorideHCID 86695423N-(5-Bromo-benzothiazol-2-ylmethyl)-methanesulfonamideHCID 866954252,2-Difluoro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)-ethyl]-acetamide

생성물 1

HCID 866954242,2-Difluoro-N-((1S,2R)-1-fluoromethyl-2-hydroxy-2-{4-[2-(methanesulfonylamino-methyl)-benzothiazol-5-yl]-phenyl}-ethyl)-acetamide수율 1.6%

시약·촉매·용매 3

HCID 178418476HCID 178418476, 화합물촉매
HCID 962Water용매
HCID 13387N-methyl-2-pyrrolidone용매

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온도
90 °C

실험 절차

To a stirred solution of N-(5-Bromo-benzothiazol-2-ylmethyl) methane sulfonamide (0.21 g, 0.656 mmol) and 2,2-Difluoro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)-ethyl]-acetamide (0.404 g, 0.984 mmol) in N-Methyl-2-pyrrolidone (9 mL) is added lithium chloride (0.084 g, 1.968 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 15 minutes then Pd(PPh3)2Cl2 (0.046 g, 0.065 mmol) is added. The reaction mixture heated to 90° C. for 16 hours. Reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulfate, solvent is evaporated in vacuo to give the crude material purified by flash column chromatography using 2.4% methanol in CH2Cl2 as an eluent to give impure compound. The impure compound is again purified by prep-HPLC to give the title compound (5 mg). 1HNMR (400 MHz, DMSO) δ: 3.04 (s, 3H), 4.26-4.33 (m, 1H), 4.41-4.43 (m, 0.5H), 4.44-4.50 (m, 0.5H), 4.62 (s, 2H), 4.65-4.68 (m, 0.5H), 4.75-4.79 (m, 0.5H), 4.87-4.88 (m, 1H), 5.9 (d, J=4.56 Hz, 1H), 6.20 (d, J=56.36 Hz, 1H), 7.45 (d, J=8.24 Hz, 2H), 7.63, (d, J=8.16 Hz, 1H), 7.73 (d, J=8.28 Hz, 2H). 7.81 (d, J1=1.8 Hz, J2=8.52 Hz, 1H), 8.42 (d, J=1.6 Hz, 1H), 8.82-8.83 (m, 2H). LC-Ms (m/z): [M−H]=485.8.

후처리

  1. customResulting
  2. customreaction mixture
  3. customis degassed with nitrogen for 15 minutes
  4. customReaction mixture
  5. temperatureis cooled to room temperature
  6. extractionextracted with ethyl acetate
  7. dry with materialOrganic layer is dried over sodium sulfate, solvent
  8. customis evaporated in vacuo
  9. customto give the crude material
  10. custompurified by flash column chromatography
  11. customto give impure compound
  12. customThe impure compound is again purified by prep-HPLC

출처 및 근거

ORD 기록
ord-a8b6888837e24389baf3a258898c9c4a
출처 데이터셋
uspto-grants-2016_08
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09428528B2

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