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Water → 5-(4-{5-[(4-Fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyrazin-2-amine

HRID 241171
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HRID 241171 반응식
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24](B5OC(C)(C)C(C)(C)O5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[NH2:36][C:37]1[CH:42]=[N:41][C:40](Br)=[CH:39][N:38]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:40]5[N:41]=[CH:42][C:37]([NH2:36])=[N:38][CH:39]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1
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참가 물질

7

반응물 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 5995392-Amino-5-bromopyrazineHCID 668205164-(5-[(4-Fluorophenyl)methyl]-6-methylpyrimidin-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine

생성물 1

HCID 573893405-(4-{5-[(4-Fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyrazin-2-amine
수율 20%

시약·촉매·용매 2

HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 6228Dimethylformamide용매

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온도
95 °C

실험 절차

A solution of 4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.10 g, 0.21 mmol), 2-amino-5-bromopyrazine (40 mg, 0.21 mmol) and potassium carbonate (0.12 g, 0.84 mmol) in N,N-dimethylformamide (5 mL), and water (0.5 mL) was degassed by bubbling nitrogen gas for five minutes followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.021 mmol), then stirred at 95° C. for 16 hours. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (30 mL). The organic layer was separated, washed with brine, dried over sodium sulfate then filtered and concentrated. Purification by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided 5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyrazin-2-amine (18 mg, 20%). 1H NMR (400 MHz, d6-DMSO): 8.80 (s, 1H), 8.38 (s, 1H), 7.96 (s, 1H), 7.72 (d, 1H), 7.50 (br s, 1H), 7.25-7.14 (m, 4H), 6.93 (d, 1H), 4.90 (s, 2H), 4.32 (m, 2H), 4.00 (m, 4H), 2.22 (s, 3H). MS (EI) for C25H23FNO6: 443 (MH+).

후처리

  1. customby bubbling nitrogen gas for five minutes
  2. temperatureAfter cooling to room temperature the reaction mixture
  3. customwas partitioned between ethyl acetate (50 mL) and brine (30 mL)
  4. customThe organic layer was separated
  5. washwashed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationthen filtered
  8. concentrationconcentrated
  9. customPurification by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile)

출처 및 근거

ORD 기록
ord-7471236f89dd48e69f27488f159621a4
출처 데이터셋
uspto-grants-2014_02
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08648066B2

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