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 474057노트

반응식

HRID 474057 반응식
[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]

참가 물질

9

반응물 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

생성물 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

시약·촉매·용매 4

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 962Water용매HCID 15413tert-Butyl methyl ether용매HCID 312751,4-Dioxane용매

반응 조건

온도
40 °C

실험 절차

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 Pd2 dba3 (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).

후처리

  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)

출처 및 근거

ORD 기록
ord-e90fdb8152264aea9e86f7deb2468ec2
출처 데이터셋
uspto-grants-2014_01
특허 번호
US08637508B2

반응 노트

불러오는 중…