Potassium Phosphate, Tribasic → 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 72006

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HRID 72006 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:64])[NH:28][CH:29]([C:33]([N:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[C:40]1[NH:41][C:42]([C:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[C:50](B4OC(C)(C)C(C)(C)O4)[CH:51]=3)[CH:46]=2)=[CH:43][N:44]=1)=[O:34])[CH:30]([CH3:32])[CH3:31].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>COCCOC.CCOC(C)=O.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:50]3[CH:49]=[CH:48][C:47]4[C:52](=[CH:53][CH:54]=[C:45]([C:42]5[NH:41][C:40]([CH:36]6[CH2:37][CH2:38][CH2:39][N:35]6[C:33](=[O:34])[CH:29]([NH:28][C:27]([O:26][CH3:25])=[O:64])[CH:30]([CH3:32])[CH3:31])=[N:44][CH:43]=5)[CH:46]=4)[CH:51]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

참가 물질

8

반응물 4

HCID 62657Potassium Phosphate, TribasicHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 547756232-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl esterHCID 66620765[2-Methyl-1-(2-{4-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester

생성물 1

HCID 666204642-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester수율 50.8%

시약·촉매·용매 3

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 80711,2-Dimethoxyethane용매HCID 21584119Ethylacetate methanol용매

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온도
80 °C

실험 절차

To a solution of 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.5 mmol) and [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (1.97 g, 3.6 mmol, 1.5 equiv.) in DME (12.5 mL) was added K3PO4 (aqueous, 2 M, 3.9 mL, 7.8 mmol, 3 equiv.), Pd2 dba3 (0.12 g, 0.13 mmol, 0.05 equiv.), and Xantphos (0.15 g, 0.26 mmol, 0.1 equiv.). The slurry was degassed with argon for 5 minutes and heated to 80° C. for 18 hours. The resulting reaction mixture was diluted with EtOAc/MeOH (10:1) and filtered through CELITE. The solution was washed with water and brine. The aqueous layer was back-extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 50→100% EtOAc in Hexanes) to provide 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.93 g, 49%) as a yellow powder. LCMS-ESI+: calc'd for C42H49N7O5: 731.4 (M+). Found: 732.9 (M+H+).

후처리

  1. customThe slurry was degassed with argon for 5 minutes
  2. customThe resulting reaction mixture
  3. filtrationfiltered through CELITE
  4. washThe solution was washed with water and brine
  5. extractionThe aqueous layer was back-extracted with EtOAc
  6. dry with materialthe combined organic layers were dried over Na2SO4
  7. concentrationconcentrated
  8. customThe crude oil was purified by column chromatography (SiO2, 50→100% EtOAc in Hexanes)

출처 및 근거

ORD 기록
ord-5d7353123f75466bae59ff8087280517
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08822430B2

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