Hydrochloric Acid → 1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-ethanone

HRID 230264

반응식

HRID 230264 반응식
CO[C:3](=[O:22])[CH2:4][C:5]1[N:9]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[O:33]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH2:35][CH:34]1C(Cl)=O.Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(O)(=O)C>[O:33]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH2:35][CH:34]1[C:3](=[O:22])[CH2:4][C:5]1[N:9]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1

참가 물질

8

반응물 5

HCID 313Hydrochloric AcidHCID 11430Potassium Carbonate2회HCID 27354472,3-Dihydro-1,4-benzodioxin-2-carbonyl chlorideHCID 3251421Potassium bis(trimethylsilyl)amideHCID 9839075Methyl 2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetate

생성물 1

HCID 113154961-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-ethanone수율 2%

시약·촉매·용매 2

HCID 176Acetic Acid용매HCID 8028Tetrahydrofuran용매2회

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온도
-78 °C

실험 절차

(6-Methyl-2-p-tolyl-imidazo[1,2,a]pyridin-3-yl)-acetic acid methyl ester 35a (447 mg, 1.5 mmol) was dissolved in anhydrous THF (15 mL) and cooled to −78° C. Potassium hexamethyldisilazide (0.5M in toluene, 3.0 mL, 1.5 mmol) was added slowly and the resulting bright orange solution was stirred at −78° C. for 10 minutes. 2,3-Dihydro-benzo[1,4]dioxine-2-carbonyl chloride (150 mg, 0.76 mmol) dissolved in anhydrous THF (10 mL) was added dropwise to the enolate solution. The resulting yellow solution was stirred for 1 h at −78° C. and quenched with H2O (30 mL). After the solution warmed to room temperature, it was washed with EtOAc (3×30 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. The crude keto-ester (0.76 mmol) was dissolved in concentrated acetic acid (4.5 mL) and concentrated HCl (4.5 mL). A reflux condenser was attached and the yellow solution was heated at 120° C. for 16 h. The solution was cooled to room temperature and saturated aqueous K2CO3 was added slowly until pH=6. The suspension was poured into saturated aqueous K2CO3 and washed with EtOAc (3×50 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. Purification was affected via silica gel column chromatography with 0-5% MeOH/CH2Cl2, then semi preparative reverse phase HPLC. Conditions: 20 mL/min flow rate, gradient of 40-80% CH3CN/H2O over 20 minutes, monitoring at 254 nm. The product eluted at 14.3 minutes. Product fractions were collected and concentrated to remove CH3CN, then washed with EtOAc (3×30 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. Final purification by silica gel column chromatography with 0-5% MeOH/CH2Cl2 yielded 1-(2,3-Dihydro-benzo [1,4]dioxin-2-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-ethanone (6.0 mg, 2%) as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.56-7.50 (m, 3H), 7.42 (s, 1H), 7.23 (d, J=8.07, 2H), 7.04 (dd, J=1.1, 9.2 Hz, 1H), 6.95-6.89 (m, 4H), 4.82-4.80 (m, 1H), 4.51-4.42 (m, 2H), 4.33-4.26 (m, 2H), 2.40 (s, 3H), 2.31 (s, 3H). Mass spectrum (m/e) 399 (M+1)+.

후처리

  1. stirringThe resulting yellow solution was stirred for 1 h at −78° C.
  2. customquenched with H2O (30 mL)
  3. temperatureAfter the solution warmed to room temperature
  4. washit was washed with EtOAc (3×30 mL)
  5. dry with materialThe combined organic washes were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customA reflux condenser was attached
  9. temperaturethe yellow solution was heated at 120° C. for 16 h
  10. temperatureThe solution was cooled to room temperature
  11. washwashed with EtOAc (3×50 mL)
  12. dry with materialThe combined organic washes were dried (Na2SO4)
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customPurification
  16. waitConditions: 20 mL/min flow rate, gradient of 40-80% CH3CN/H2O over 20 minutes
  17. washThe product eluted at 14.3 minutes
  18. customProduct fractions were collected
  19. concentrationconcentrated
  20. customto remove CH3CN
  21. washwashed with EtOAc (3×30 mL)
  22. dry with materialThe combined organic washes were dried (Na2SO4)
  23. filtrationfiltered
  24. concentrationconcentrated
  25. customFinal purification by silica gel column chromatography with 0-5% MeOH/CH2Cl2

출처 및 근거

ORD 기록
ord-6d40056bbf634a478bd50c617b8092f8
출처 데이터셋
uspto-grants-2009_07
특허 번호
US07566725B2

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