Nitrogen → 3-{5-[4-(4-[2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

HRID 79870노트

반응식

HRID 79870 반응식
[CH3:1][O:2][C:3](=[O:29])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:30]([O:34][C:35]([N:37]1[CH:42]([C:43]2[NH:44][C:45]([C:48]3[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=3)=[CH:46][N:47]=2)[CH:41]2[CH2:55][CH:38]1[CH2:39][CH2:40]2)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C.N#N>CN(C=O)C.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.[Cu]I.CO.CCOC(C)=O>[C:30]([O:34][C:35]([N:37]1[CH:42]([C:43]2[NH:44][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:28]#[C:27][C:24]4[CH:25]=[CH:26][C:21]([C:18]5[NH:17][C:16]([CH:12]6[CH2:13][CH2:14][CH2:15][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:29])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=5)=[CH:22][CH:23]=4)=[CH:50][CH:49]=3)=[CH:46][N:47]=2)[CH:41]2[CH2:55][CH:38]1[CH2:39][CH2:40]2)=[O:36])([CH3:33])([CH3:31])[CH3:32]

참가 물질

9

반응물 4

HCID 947NitrogenHCID 8471TriethylamineHCID 596109073-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterHCID 72338228(1-{2-[4-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

생성물 1

HCID 666207333-{5-[4-(4-[2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester수율 54%

시약·촉매·용매 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)촉매HCID 178418397HCID 178418397, 화합물촉매HCID 6228Dimethylformamide용매HCID 21584119Ethylacetate methanol용매

반응 조건

온도
80 °C

실험 절차

A solution of (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (500 mg, 1.27 mmol), 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (530 mg, 1.27 mmol), and triethylamine (531 □L, 3.81 mmol) in DMF (6.4 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (150 mg, 0.13 mmol) and CuI (25 mg, 0.13 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was quenched with AcOH then purified by reverse phase preparative HPLC (10-70% MeCN—H2O; 0.1% formic acid modifier) then silica gel chromatography (0-10% MeOH-EtOAc gradient) to afford 3-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (500 mg, 0.68 mmol, 54% yield). LCMS-ESI+: calc'd for C42H50N7O5: 732.4 (M+H+). Found: 732.2 (M+H+).

후처리

  1. customThe pressure flask was sealed
  2. temperatureAfter cooling to room temperature
  3. customthe reaction was quenched with AcOH
  4. customthen purified by reverse phase preparative HPLC (10-70% MeCN—H2O; 0.1% formic acid modifier)

출처 및 근거

ORD 기록
ord-aabad3f050894490b3303c8722ea709e
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08841278B2

반응 노트

불러오는 중…