Cesium carbonate → ((2R,5R)-5-{6-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester

HRID 538318ノート

反応式

HRID 538318 の反応式
[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([C:30]1[CH:31]=[C:32]([CH3:39])[C:33]([C:36]([NH2:38])=[O:37])=[N:34][CH:35]=1)#[N:29].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CC(OC)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:38][C:36]([C:33]3[C:32]([CH3:39])=[CH:31][C:30]([C:28]#[N:29])=[CH:35][N:34]=3)=[O:37])[N:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]

参加物

9

反応物 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 666659355-Cyano-3-methyl-2-pyridinecarboxamideHCID 86668028[(2R,5R)-5-(6-Bromo-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester

生成物 1

HCID 68108079((2R,5R)-5-{6-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester

試薬・触媒・溶媒 4

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 962Water溶媒HCID 15413tert-Butyl methyl ether溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
40 °C

実験手順

A mixture of [(2R,5R)-5-(6-Bromo-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (60.00 mg, 0.133 mmol), 5-cyano-3-methylpicolinamide (23.52 mg, 0.146 mmol), Xantphos (6.91 mg, 0.012 mmol) and Cs2CO3 (60.50 mg, 0.186 mmol) in dioxane (0.611 ml) was degassed with argon for 5 min, then Pd2dba3 (3.64 mg, 3.98 μmol) was added and the reaction mixture was stirred at 40° C. for 18 h. The reaction mixture was diluted with H2O and TBME. The phases were separated and the aq. phase was reextracted with TBME. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. HPLC purification (Alltech Grom Saphir 65 Si 10 μM column, 150×30 mm, gradient n-heptane:EtOAc 0-1.2 min 75:25, 1.2-9 min 0:100, 9-12 min 0:100, flow: 50 ml/min, detection: 254 nm) yielded the title compound as a colourless solid. HPLC RtH4=1.37 min; ESIMS: 533 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 11.22 (s, 1H), 10.47 (s, 1H), 8.78 (d, 1H), 8.33 (d, 1H), 7.98 (d, 1H), 7.84-7.80 (m, 1H), 7.13 (d, 1H), 4.37 (d, 1H), 4.11 (d, 1H), 2.88 (s, 3H), 1.64 (s, 3H), 1.57 (br s, 12H).

後処理

  1. customwas degassed with argon for 5 min
  2. customThe phases were separated
  3. washphases were washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customHPLC purification (Alltech Grom Saphir 65 Si 10 μM column, 150×30 mm, gradient n-heptane:EtOAc 0-1.2 min 75:25, 1.2-9 min 0:100, 9-12 min 0:100, flow: 50 ml/min, detection: 254 nm)

出典と根拠

ORDレコード
ord-8f9a0c672c4a40309222e796efd692ef
出典データセット
uspto-grants-2014_10
特許番号
US08865712B2

反応ノート

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