Sodium Carbonate → (R)-tert-Butyl 2-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate

HRID 384715ノート

反応式

HRID 384715 の反応式
[H-].[Na+].ClC1C=C(N)C(I)=CN=1.S(OC[C@@H]1OCCN(C(OC(C)(C)C)=O)C1)(C1C=CC(C)=CC=1)(=O)=O.[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41](I)=[CH:40][N:39]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:66][O:67][C:68]1[CH:73]=[CH:72][C:71](B(O)O)=[CH:70][CH:69]=1>CN(C=O)C.C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41]([C:71]2[CH:72]=[CH:73][C:68]([O:67][CH3:66])=[CH:69][CH:70]=2)=[CH:40][N:39]=1

参加物

11

反応物 6

HCID 10340Sodium CarbonateHCID 24758Sodium hydride2 回HCID 201262(4-Methoxyphenyl)boronic acidHCID 454803662-Chloro-5-iodopyridin-4-amineHCID 54043639(R)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylateHCID 86648391(R)-tert-butyl 2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate

生成物 1

HCID 59613416(R)-tert-Butyl 2-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate収率 94.3%

試薬・触媒・溶媒 4

HCID 11979704Tetrakis(triphenylphosphine)palladium触媒HCID 962Water溶媒HCID 6228Dimethylformamide溶媒2 回HCID 6342Acetonitrile溶媒

反応条件

温度
80 °C

実験手順

NaH (0.024 g, 0.569 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (0.121 g, 0.474 mmol) in DMF (2.8 mL) at room temperature and stirred for 10 min. The temperature was raised to 80° C. and (R)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate (0.264 g, 0.711 mmol) in DMF (0.6 mL) was added. The reaction mixture was stirred for 2 h before further NaH (0.024 g, 0.569 mmol) was added at room temperature. The reaction mixture was heated at 80° C. for a further 1 h then cooled. Water was added and the mixture was partitioned between ethyl acetate (20 mL) and aq. NaHCO3 (20 mL). The organic phase was washed with brine, dried (MgSO4) and concentrated. The mixture was purified by flash column chromatography on silica gel, eluting with ethyl acetate and hexane (2/4), to give an inseparable mixture of starting material and product. LC-MS (4) Rt=2.66 min; m/z (ESI+) 397 [MH+]. A solution of the crude (R)-tert-butyl 2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate (0.040 g, 0.088 mmol), sodium carbonate (0.5 M, 0.26 mL), 4-methoxyphenyl boronic acid (0.013 g, 0.088 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.011 g, 0.01 mmol) in acetonitrile (2 mL) was heated under microwave irradiation at 100° C. for 20 min. The reaction mixture was concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1/1), to give the title compound as colorless oil (0.036 g, 94%).

後処理

  1. additionwas added at room temperature
  2. temperatureThe reaction mixture was heated at 80° C. for a further 1 h
  3. temperaturethen cooled
  4. customthe mixture was partitioned between ethyl acetate (20 mL) and aq. NaHCO3 (20 mL)
  5. washThe organic phase was washed with brine
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated
  8. customThe mixture was purified by flash column chromatography on silica gel
  9. washeluting with ethyl acetate and hexane (2/4)
  10. customto give
  11. additionan inseparable mixture of starting material and product
  12. concentrationThe reaction mixture was concentrated in vacuo
  13. customThe mixture was purified by flash column chromatography on silica gel
  14. washeluting with ethyl acetate/hexane (1/1)

出典と根拠

ORDレコード
ord-397f8314b3d740f7845ca002148fdbf5
出典データセット
uspto-grants-2013_02
特許番号
US08367658B2

反応ノート

読み込み中…