1-isopropyl-3-methyl-1H-1,2,4-triazole → 9-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene

HRID 1530406노트

반응식

HRID 1530406 반응식
[CH:1]([N:4]1[CH:8]=[N:7][C:6]([CH3:9])=[N:5]1)([CH3:3])[CH3:2].C(N1C(C)=NC=N1)(C)C.C([Li])CCC.[Br:24][C:25]1[C:26]([CH3:40])=[CH:27][C:28]2[O:37][CH2:36][CH2:35][N:34]3[C:30](=[N:31][C:32](I)=[CH:33]3)[C:29]=2[CH:39]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[Br:24][C:25]1[C:26]([CH3:40])=[CH:27][C:28]2[O:37][CH2:36][CH2:35][N:34]3[C:30](=[N:31][C:32]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:9])[N:7]=4)=[CH:33]3)[C:29]=2[CH:39]=1

참가 물질

8

반응물 4

HCID 207448981-isopropyl-3-methyl-1H-1,2,4-triazoleHCID 540510601-isopropyl-5-methyl-1H-[1,2,4]triazoleHCID 6831288010-Bromo-2-iodo-9-methyl-5,6-dihydrobenzo[F]imidazo[1,2-D][1,4]oxazepineHCID 178418339Butyllithium

생성물 1

HCID 683128519-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene수율 35%

시약·촉매·용매 3

HCID 3007855Zincchloride촉매HCID 178418397HCID 178418397, 화합물촉매HCID 8028Tetrahydrofuran용매2회

반응 조건

온도
-30 °C

실험 절차

A solution of 1-isopropyl-3-methyl-1H-[1,2,4]triazole (in a 6:4 mixture with 1-isopropyl-5-methyl-1H-[1,2,4]triazole, 0.292 g, 1.4 mmol) in THF (5 mL) was cooled to −30° C. and treated with n-butyllithium (2.5M in hexanes, 0.56 mL, 1.40 mmol). Stirring was continued for 1 h maintaining the internal temperature between −30° C. and −20° C. The mixture was then cooled to −30° C. and a solution of zinc chloride (0.5M in THF, 1.66 mL, 0.83 mmol) was added over 2 min. The reaction mixture was then slowly warmed to RT over 1 h. A solution of 9-bromo-2-iodo-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (404 mg, 1.0 mmol) in THF (5 mL) was added followed by Pd(PPh3)4 (58 mg, 0.128 mmol) and the reaction mixture was stirred at 60° C. under a nitrogen atmosphere for 18 h. After cooling to RT, volatiles were removed in vacuo and the residue was partitioned between EtOAc (300 mL) and water. The aqueous phase was further extracted with EtOAc (300 mL) and the combined organic layers were washed with water followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent 100% EtOAc followed by gradient 1-10% MeOH in EtOAc) affording the title compound (0.168 g, 35%). LCMS: RT 3.71 min [M+H]+ 402.0/404.0. 110178153

후처리

  1. temperaturemaintaining the internal temperature between −30° C. and −20° C
  2. temperatureThe reaction mixture was then slowly warmed to RT over 1 h
  3. stirringthe reaction mixture was stirred at 60° C. under a nitrogen atmosphere for 18 h
  4. temperatureAfter cooling to RT
  5. customvolatiles were removed in vacuo
  6. customthe residue was partitioned between EtOAc (300 mL) and water
  7. extractionThe aqueous phase was further extracted with EtOAc (300 mL)
  8. washthe combined organic layers were washed with water
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated in vacuo
  11. customThe resulting residue was purified by column chromatography (Si-PCC, eluent 100% EtOAc followed by gradient 1-10% MeOH in EtOAc)

출처 및 근거

ORD 기록
ord-b702cd5ab06345ddae6596128b3b9608
출처 데이터셋
uspto-grants-2015_07
특허 번호
US09090628B2

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