Nitrogen → 3-{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}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

HRID 71923

반응식

HRID 71923 반응식
[CH3:1][O:2][C:3](=[O:40])[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:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26](B4OC(C)(C)C(C)(C)O4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:41]([O:45][C:46]([N:48]1[CH:53]([C:54]2[NH:55][C:56]([C:59]3[CH:64]=[CH:63][C:62](Br)=[CH:61][CH:60]=3)=[CH:57][N:58]=2)[CH:52]2[CH2:66][CH:49]1[CH2:50][CH2:51]2)=[O:47])([CH3:44])([CH3:43])[CH3:42].C([O-])([O-])=O.[K+].[K+].N#N>COCCOC.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>[C:41]([O:45][C:46]([N:48]1[CH:53]([C:54]2[NH:55][C:56]([C:59]3[CH:64]=[CH:63][C:62]([C:26]4[CH:25]=[CH:24][C:23]5[C:28](=[CH:29][CH:30]=[C:21]([C:18]6[NH:17][C:16]([CH:12]7[CH2:13][CH2:14][CH2:15][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:40])[CH:6]([CH3:7])[CH3:8])=[N:20][CH:19]=6)[CH:22]=5)[CH:27]=4)=[CH:61][CH:60]=3)=[CH:57][N:58]=2)[CH:52]2[CH2:66][CH:49]1[CH2:50][CH2:51]2)=[O:47])([CH3:44])([CH3:42])[CH3:43]

참가 물질

7

반응물 4

HCID 947NitrogenHCID 11430Potassium CarbonateHCID 596109073-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-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 666214363-{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}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester수율 16.3%

시약·촉매·용매 2

HCID 178418397HCID 178418397, 화합물촉매HCID 80711,2-Dimethoxyethane용매

반응 조건

온도
80 °C

실험 절차

A solution of [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 (500 mg, 0.92 mmol), 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (383 mg, 0.92 mmol) and aq K2CO3 (920 μl of a 2M solution, 1.84 mmol) in DME (9 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (106 mg, 0.092 mmol) and PdCl2dppf (75 mg, 0.092 mmol) and then the reaction was heated to 80° C. overnight. After cooling to room temperature, the reaction was quenched with acetic acid, filtered, and then concentrated. The crude product was purified by reverse phase preparative HPLC (5-50% MeCN—H2O; 0.1% formic acid modifier) to afford 3-{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}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (112 mg, 0.15 mmol, 16% yield). LCMS-ESI+: calc'd for C44H52N7O5: 758.4 (M+H+). Found: 758.0 (M+H+).

후처리

  1. temperatureAfter cooling to room temperature
  2. customthe reaction was quenched with acetic acid
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude product was purified by reverse phase preparative HPLC (5-50% MeCN—H2O; 0.1% formic acid modifier)

출처 및 근거

ORD 기록
ord-2fd133cdee174e2b97d261d542659c6f
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08822430B2

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