6-bromo-2H,3H,4H-pyrido(3,2-b)(1,4)oxazine → (R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one

HRID 2209099노트

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HRID 2209099 반응식
[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[CH:33]=[CH:34][C:35]2[O:36][CH2:37][CH2:38][NH:39][C:40]=2[N:41]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[CH:33]=[CH:34][C:35]5[O:36][CH2:37][CH2:38][NH:39][C:40]=5[N:41]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1

참가 물질

6

반응물 2

HCID 208243766-bromo-2H,3H,4H-pyrido(3,2-b)(1,4)oxazineHCID 123319683(R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one

생성물 1

HCID 117843286(R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one수율 34%

시약·촉매·용매 3

HCID 178418397HCID 178418397, 화합물촉매HCID 80711,2-Dimethoxyethane용매HCID 10340Sodium Carbonate용매

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온도
135 °C

실험 절차

In a 10 ml microwave reactor vial were placed (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (150.0 mg, 0.36 mmol), 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (172.5 mg, 0.8 mmol), and Pd(PPh3)4 (21.1 mg, 0.02 mmol) in DME (1 ml) and 2N Na2CO3 (1 ml). The mixture was sonicated and degassed for 1 min, placed in the microwave reactor, and heated at 135° C. for 15 min. Then it was directly loaded onto the pre-packed silica cartridge and purified using flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane). The fractions were collected, concentrated, and further purified by reverse phase flash chromatography. The fractions were collected, neutralized with sat. NaHCO3, and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated to give 52.7 mg (34%) of (R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.06 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.60 (s, 1H), 7.39 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.74 (s, 1H), 4.76 (m, 1H), 4.13 (m, 2H), 3.67 (m, 1H), 3.42 (m, 3H), 3.19 (m, 1H), 2.82 (m, 1H), 2.36 (m, 2H), 1.31 (d, J=5.8 Hz, 3H), 1.05 (m, 4H). MS (ESI+) m/z 420.2 (M+H).

후처리

  1. customIn a 10 ml microwave reactor vial were placed
  2. customThe mixture was sonicated
  3. customdegassed for 1 min
  4. custompurified
  5. customThe fractions were collected
  6. concentrationconcentrated
  7. customfurther purified by reverse phase flash chromatography
  8. customThe fractions were collected
  9. extractionextracted with EtOAc
  10. washThe combined organic layers were washed with water and brine
  11. dry with materialdried (Na2SO4)
  12. filtrationfiltered
  13. concentrationconcentrated

출처 및 근거

ORD 기록
ord-895517f85e6e4176b411a67d20923a5e
출처 데이터셋
uspto-grants-2016_06
특허 번호
US09376441B2

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