Water → 6-(5-morpholino-3-pyridyl)-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide

HRID 712678

反応式

HRID 712678 の反応式
CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)O1.Br[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[O:33]1[CH2:34][CH2:35][N:30]([C:26]2[CH:25]=[C:24]([C:9]3[CH:10]=[C:11]4[C:16](=[N:17][CH:18]=3)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]4)[CH:29]=[N:28][CH:27]=2)[CH2:31][CH2:32]1

参加物

6

反応物 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 467396144-(5-Bromopyridin-3-yl)morpholineHCID 1231626313,4-Dihydro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-1(2h)-carboxamide

生成物 1

HCID 1176675166-(5-morpholino-3-pyridyl)-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide

試薬・触媒・溶媒 1

HCID 312751,4-Dioxane溶媒

反応条件

温度
90 °C

実験手順

In a sealed tube which contains the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (generated according to the procedure for Step 3 of Example 16 in 5 ml 1,4-dioxane, 0.78 mmol) is added 4-(5-bromo-pyridin-3-yl)-morpholine (228 mg, 0.94 mmol), Na2CO3 (166 mg, 1.56 mmol) and water (1.0 ml). The mixture is bubbled with Argon for 5 min. Then PdCl2(DPPF) DCM complex (64 mg, 0.078 mmol) is added. The mixture is then bubbled with Argon for 5 min. The cap is sealed and the mixture is heated at 90° C. in oil bath for 1 h. The reaction mixture is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is extracted with DCM. The combined DCM phases are concentrated. The crude is purified by flash silica gel column (MeOH/DCM 0 to 4% gradient, then 4%). The fractions which contain the desired product are combined, concentrated and further purified by C-18 prep HPLC (MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 45% gradient over 10 min run). The desired fractions are combined and basified by 1N Na2CO3 to pH=10, and are extracted by DCM. The DCM phases are combined and concentrated under vacuum to obtain 60 mg of the title compound.

後処理

  1. customIn a sealed tube which contains
  2. customThe mixture is bubbled with Argon for 5 min
  3. additionThen PdCl2(DPPF) DCM complex (64 mg, 0.078 mmol) is added
  4. customThe mixture is then bubbled with Argon for 5 min
  5. customThe cap is sealed
  6. temperatureThe reaction mixture is cooled to room temperature
  7. filtrationThe reaction mixture is filtered through diatomaceous earth
  8. washwashed with DCM
  9. customThe filtrate is partitioned between water and DCM
  10. extractionThe aqueous phase is extracted with DCM
  11. concentrationThe combined DCM phases are concentrated
  12. customThe crude is purified by flash silica gel column (MeOH/DCM 0 to 4% gradient
  13. concentrationconcentrated
  14. customfurther purified by C-18 prep HPLC (MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 45% gradient over 10 min run)
  15. extractionare extracted by DCM
  16. concentrationconcentrated under vacuum

出典と根拠

ORDレコード
ord-5f07f103ef604dae87d3533b62b2f969
出典データセット
uspto-grants-2015_11
特許番号
US09181272B2

関連ノート

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