Sodium Carbonate → 5-[3-((4R,5R)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-nicotinonitrile

HRID 1626115노트

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HRID 1626115 반응식
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[N:51][CH:52]=[C:53]([CH:56]=2)[C:54]#[N:55])O1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([C:49]4[CH:50]=[N:51][CH:52]=[C:53]([CH:56]=4)[C:54]#[N:55])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1

참가 물질

7

반응물 4

HCID 10340Sodium CarbonateHCID 11776TriphenylphosphineHCID 164142165-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrileHCID 71008920[bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine

생성물 1

HCID 710088825-[3-((4R,5R)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-nicotinonitrile수율 100.1%

시약·촉매·용매 2

HCID 167845palladium(II) acetate촉매HCID 80711,2-Dimethoxyethane용매

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온도
105 °C

실험 절차

In a dry tube under an atmosphere of argon to a solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.3) (250 mg, 412 μmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (142 mg, 617 μmol) in 1,2-dimethoxyethane (3 ml) were added consecutively an aqueous solution of sodium carbonate (2M, 0.6 ml), triphenylphosphine (22.3 mg, 82.3 μmol), and, after flushing the mixture with argon, palladium(II)acetate (9.24 mg, 41.2 μmol). The tube was sealed and heated under stirring at 105° C. for 15 hours. After evaporation at reduced pressure, the residue was purified by chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 60:30 as the eluent. The 5-[3-((4R,5R)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-nicotinonitrile (260 mg, 100% yield) as a white foam. MS (ISP): m/z=631.4 [M+H]+.

후처리

  1. customThe tube was sealed
  2. temperatureheated
  3. customAfter evaporation at reduced pressure
  4. customthe residue was purified by chromatography on a silica-NH2 phase

출처 및 근거

ORD 기록
ord-3bea39cf69f340d3a2ff5881ff4a22b2
출처 데이터셋
uspto-grants-2014_07
특허 번호
US08785436B2

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