Potassium Carbonate → 5-{[6-(2-Hydroxy-1-morpholin-4-ylethyl)pyridin-2-yl]amino}-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamide

HRID 2060638ノート

反応式

HRID 2060638 の反応式
[NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:19]([NH2:21])=[O:20].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].Br[C:63]1[N:68]=[C:67]([CH:69]([N:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)[CH2:70][OH:71])[CH:66]=[CH:65][CH:64]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:71][CH2:70][CH:69]([C:67]1[N:68]=[C:63]([NH:1][C:2]2[S:6][C:5]([C:7]3[CH:8]=[N:9][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:11][CH:12]=3)=[N:4][C:3]=2[C:19]([NH2:21])=[O:20])[CH:64]=[CH:65][CH:66]=1)[N:72]1[CH2:77][CH2:76][O:75][CH2:74][CH2:73]1

参加物

6

反応物 4

HCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 583352605-Amino-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamideHCID 583352752-(6-Bromopyridin-2-yl)-2-morpholin-4-ylethanol

生成物 1

HCID 451019395-{[6-(2-Hydroxy-1-morpholin-4-ylethyl)pyridin-2-yl]amino}-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamide

試薬・触媒・溶媒 1

HCID 9811564Bis(dibenzylideneacetone)palladium触媒

実験手順

A sealed tube was charged with a stir bar, 5-amino-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamide (100 mg, 0.33 mmol), Pd2(dba)3 (30.0 mg, 0.033 mmol), X-PHOS (78 mg, 0.16 mmol), and potassium carbonate (50 mg, 0.36 mmol). The tube was evacuated and backfilled with argon (3×). 2-(6-Bromopyridin-2-yl)-2-morpholin-4-ylethanol (Enantiomer B) (Example 3, Step 1, chiral separation) (94 mg, 0.33 mmol) was placed in a separate vial which was also evacuated and backfilled with argon (3×). Fully degassed tert-amyl alcohol (1.5 mL) was added to the vial containing 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (Enantiomer B) and the resulting solution was transferred to the sealed tube containing the rest of the reactants. This tube was then sealed and placed in an oil bath at 100° C. and stirred overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification via flash chromatography (silica, 0-15% methanol/ethyl acetate) afforded the title compound as a yellow powder. 1H NMR (500 MHz, d6-DMSO): δ 11.21 (s, 1H), 8.66 (d, 1H), 8.08 (dd, 1H), 7.72 (s, 1H), 7.69 (t, 1H), 7.59 (s, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.93 (d, 1H), 4.53 (m, 1H), 3.99 (m, 2H), 3.70 (m, 4H), 3.66 (m, 1H), 3.54 (m, 8H), 2.51 (m, 4H). LRMS (APCI) calc'd for C24H30N7O4S [M+H]+ 512.2, found 512.1. τr=13.5 min using supercritical fluid chromatography supercritical fluid chromatography (CO2, AD-H column (1×25 cm, 5 um), isochratic, 40% Ethanol+0.25% isobutylamine modifier, 10 mL/min, 100 bar, 310 nM)

後処理

  1. additionA sealed tube was charged with a stir bar
  2. customThe tube was evacuated
  3. customwas also evacuated
  4. additionFully degassed tert-amyl alcohol (1.5 mL) was added to the
  5. additionvial containing 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (Enantiomer B)
  6. additioncontaining the rest of the reactants
  7. customThis tube was then sealed
  8. customplaced in an oil bath at 100° C.
  9. additiondiluted with ethyl acetate
  10. washwashed with saturated aqueous sodium bicarbonate
  11. dry with materialThe organic layer was dried over magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure
  14. customPurification via flash chromatography (silica, 0-15% methanol/ethyl acetate)

出典と根拠

ORDレコード
ord-0782396610fe4dc98856cc350885184b
出典データセット
uspto-grants-2012_10
特許番号
US08278335B2

反応ノート

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