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 2060638노트

반응식

HRID 2060638 반응식
[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

참가 물질

6

반응물 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

생성물 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

시약·촉매·용매 1

HCID 9811564Bis(dibenzylideneacetone)palladium촉매

실험 절차

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)

후처리

  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)

출처 및 근거

ORD 기록
ord-0782396610fe4dc98856cc350885184b
출처 데이터셋
uspto-grants-2012_10
특허 번호
US08278335B2

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