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1,1,3,3-Tetramethylguanidine → (R)-5,5-difluoro-4-[5-fluoro-2-(4-methoxy-benzyl)-1H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine

HRID 1626141
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인쇄 미리보기

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HRID 1626141 반응식
[NH2:1][C:2]1[C:3](I)=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.CN(C)C(N(C)C)=N.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]#[CH:38])=[CH:32][CH:31]=1>CN(C)C=O.C(=O)([O-])O.[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]2[C:3]([CH:38]=[C:37]([CH2:36][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)[NH:1]2)=[CH:4][C:5]=1[F:18])[CH3:17]
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참가 물질

8

반응물 3

HCID 664601,1,3,3-TetramethylguanidineHCID 107731151-Methoxy-4-(prop-2-yn-1-yl)benzeneHCID 58304250(R)-4-(5-amino-2-fluoro-4-iodo-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine

생성물 1

HCID 71009041(R)-5,5-difluoro-4-[5-fluoro-2-(4-methoxy-benzyl)-1H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine수율 33.4%

시약·촉매·용매 4

HCID 24350
Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)
촉매
HCID 6102075Dichlorobis(triphenylphosphine)palladium촉매
HCID 6228Dimethylformamide용매2회
HCID 516892Sodium Bicarbonate용매

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온도
80 °C

실험 절차

A solution of (R)-4-(5-amino-2-fluoro-4-iodo-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate B6.1) (100 mg, 260 μmol) N,N-dimethylformamide (0.5 ml) was purged with argon for 10 minutes. Thereafter, 1,1,3,3-tetramethylguanidine (74.8 mg, 81.3 μl, 649 μmol), bis-(triphenylphosphin)-palladium(II)dichlorid (9.11 mg, 13.0 μmol) and copper (I) iodide (7.42 mg, 38.9 μmol) were added. After 5 minutes at room temperature, a solution of 1-methoxy-4-prop-2-ynyl-benzene (CAS [13540-76-6]) (45.5 mg, 312 μmol) in N,N-dimethylformamide (0.2 ml) was added and the reaction mixture was stirred at 80° C. for 15 hours. For the workup, the reaction mixture was allowed to cool to room temperature, then it was diluted with a saturated solution of sodium hydrogencarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The crude product was purified by flash chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (R)-5,5-difluoro-4-[5-fluoro-2-(4-methoxy-benzyl)-1H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (35 mg, 33% yield) was obtained as a light green foam. MS (ISP): m/z=404.4 [M+H]+.

후처리

  1. temperatureto cool to room temperature
  2. extractionextracted with ethyl acetate
  3. dry with materialThe combined organic layers were dried over sodium sulphate
  4. customevaporated at reduced pressure
  5. customThe crude product was purified by flash chromatography on a silica-NH2 phase

출처 및 근거

ORD 기록
ord-fab20a470adc4b4b836413d3433a9f8d
출처 데이터셋
uspto-grants-2014_07
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08785436B2

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