Potassium Carbonate → (S)-3-(4-chloro-2-fluorophenyl)-8-methyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide

HRID 535968

반응식

HRID 535968 반응식
Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([NH:19][CH3:20])=[O:18])=[O:14])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1B(O)O>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd]>[Cl:38][C:36]1[CH:35]=[CH:34][C:33]([C:2]2[N:6]3[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]3=[C:4]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([NH:19][CH3:20])=[O:18])=[O:14])[N:3]=2)=[C:32]([F:31])[CH:37]=1

참가 물질

8

반응물 3

HCID 11430Potassium CarbonateHCID 4193595(4-Chloro-2-fluorophenyl)boronic acidHCID 57635259(S)-3-bromo-8-methyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide

생성물 1

HCID 57635533(S)-3-(4-chloro-2-fluorophenyl)-8-methyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide수율 40%

시약·촉매·용매 4

HCID 23938Palladium촉매HCID 11979704Tetrakis(triphenylphosphine)palladium촉매HCID 962Water용매HCID 312751,4-Dioxane용매

반응 조건

온도
110 °C

실험 절차

A mixture of intermediate 55B (47 mg, 0.12 mmol), potassium carbonate (40 mg, 0.29 mmol), 2-fluoro-4-chlorophenylboronic acid (0.25 mmol) and palladium tetrakis(triphenylphosphine) (20 mg) in dioxane (1.0 mL) and water (0.5 mL) was heated at 110° C. in a sealed vial for 4 h. After cooling down to room temperature, the mixture was passed through a thiol-based palladium scavenger resin (PolymerLabs). The residue was concentrated to dryness, to which MeOH (0.5 mL) was added. The solution was filtered to remove insoluble material and purified by prep LC-MS with 5% MeCN/water to 95 MeCN/water (0.1% formic acid) in 15 min. Pure fractions were evaporated with a Savant speedvac. The oil residue was taken up in DCM (1.0 mL) and diluted with hexane (1.0 mL). Evaporation under air flow with mild heating give white solid product Compound 529 at 40% yield. 1H-NMR (400 MHz, CDCl3) δ: 0.96 (t, J=4.8 Hz, 6H), 1.59-1.72 (m, 2H), 1.81-1.90 (m, 3H), 2.47 (s, 3H), 2.56 (br, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.98 (br, 2H), 3.96 (br, 2H), 4.52-4.58 (m, 1H), 6.48 (br, 1H), 7.21-7.24 (dd, J=2.0, 9.6 Hz, 1H), 7.29-7.31 (dd, J=1.7, 10.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H). LCMS (+ESI) m/z 450.2, 452.2 [M+H]+.

후처리

  1. temperatureAfter cooling down to room temperature
  2. concentrationThe residue was concentrated to dryness, to which MeOH (0.5 mL)
  3. additionwas added
  4. filtrationThe solution was filtered
  5. customto remove insoluble material
  6. custompurified by prep LC-MS with 5% MeCN/water to 95 MeCN/water (0.1% formic acid) in 15 min
  7. customPure fractions were evaporated with a Savant speedvac
  8. additiondiluted with hexane (1.0 mL)
  9. customEvaporation under air flow
  10. temperaturewith mild heating

출처 및 근거

ORD 기록
ord-f52304db9fc4474d8c14117a40089d36
출처 데이터셋
uspto-grants-2014_10
특허 번호
US08859538B2

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