Nitrogen → 4-[3-(3-Methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester

HRID 870745노트

반응식

HRID 870745 반응식
Br[C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.O.[CH3:26][O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1B(O)O.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.N#N>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:21]([O:20][C:18]([N:14]1[CH2:15][CH2:16][CH2:17][N:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([C:33]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[O:27][CH3:26])=[CH:3][N:4]=3)[N:7]=2)[CH2:12][CH2:13]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]

참가 물질

9

반응물 5

HCID 947Nitrogen2회HCID 6344DichloromethaneHCID 22031701Potassium phosphate, tribasic, monohydrateHCID 467390183-Methoxypyridine-4-boronic acid hydrateHCID 68647817Tert-butyl 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-1,4-diazepane-1-carboxylate

생성물 1

HCID 898025774-[3-(3-Methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester

시약·촉매·용매 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 962Water용매HCID 80711,2-Dimethoxyethane용매

반응 조건

온도
85 °C

실험 절차

To a mixture of tert-butyl 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-1,4-diazepane-1-carboxylate (329.9 mg, 0.8 mmol), (3-methoxy pyridin-4-yl)boronic acid monohydrate [1072952-50-1] (153.6 mg, 1.0 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (384.1 mg, 1.7 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (69.2 mg, 0.1 mmol) contained in a 50 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (25 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 6 h then cooled and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (MgSO4) and evaporated to afford a brown solid which was purified by preparative RP-HPLC to provide 4-[3-(3-methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester as 79.5 mg of off white powder, mp. 115-116° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotomers present) 1.01 (s, 4H) 1.20 (s, 4H) 1.91 (s, 2H) 2.51 (dt, J=3.60, 1.86 Hz, 2H) 3.27-3.35 (m, 4H) 3.57 (br. s., 1H) 3.64 (s, 1H) 3.70 (br. s., 2H) 3.81 (d, J=16.67 Hz, 2H) 4.02 (s, 3H) 7.19 (d, J=9.85 Hz, 1H) 7.93 (s, 1H) 8.11 (d, J=8.59 Hz, 1H) 8.32 (d, J=5.05 Hz, 1H) 8.49-8.54 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm (rotomers present) 13.89, 22.03, 24.66, 24.75, 27.49, 27.74, 31.20, 44.27, 44.96, 45.60, 47.99, 48.26, 48.39, 56.31, 78.25, 78.41, 109.66, 109.87, 119.88, 120.03, 120.27, 124.50, 126.00, 126.08, 134.46, 135.39, 135.52, 136.92, 141.96, 150.98, 152.56, 152.65, 154.01, 154.34. LRMS (ESI) m/z 425.2 [(M+H)]+, calc'd for C22H28N6O3: 424.51.

후처리

  1. customcontained in a 50 mL round bottomed flask
  2. customThe reaction
  3. custompot was fitted to a reflux condenser
  4. customlowered into an ambient temperature
  5. stirringThe rapidly stirred
  6. customreaction
  7. temperaturethen cooled
  8. custompartitioned between brine (
  9. customThe phase separated
  10. extractionextract
  11. dry with materialwas dried (MgSO4)
  12. customevaporated
  13. customto afford a brown solid which
  14. customwas purified by preparative RP-HPLC

출처 및 근거

ORD 기록
ord-ce95f799f9aa47d88651e9eaa6ec49b7
출처 데이터셋
uspto-grants-2015_03
특허 번호
US08969565B2

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