Nitrogen → [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl}-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester

HRID 71717

반응식

HRID 71717 반응식
[CH3:1][O:2][C:3](=[O:28])[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](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:29][O:30][C:31](=[O:68])[NH:32][CH:33]([C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44]1[NH:45][C:46]([C:49]2[CH:58]=[CH:57][C:56]3[C:51](=[CH:52][CH:53]=[C:54](B4OC(C)(C)C(C)(C)O4)[CH:55]=3)[CH:50]=2)=[CH:47][N:48]=1)=[O:38])[CH:34]([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+].N#N>C1(C)C=CC=CC=1.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.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[CH3:29][O:30][C:31](=[O:68])[NH:32][CH:33]([C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44]1[NH:45][C:46]([C:49]2[CH:58]=[CH:57][C:56]3[C:51](=[CH:52][CH:53]=[C:54]([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:28])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=5)=[CH:22][CH:23]=4)[CH:55]=3)[CH:50]=2)=[CH:47][N:48]=1)=[O:38])[CH:34]([CH3:36])[CH3:35]

참가 물질

9

반응물 4

HCID 947NitrogenHCID 11430Potassium CarbonateHCID 66620141Methyl (1-(2-(4-(4-bromophenyl)-1H-imidazol-2-YL)pyrrolidin-1-YL)-3-methyl-1-oxobutan-2-YL)carbamateHCID 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 66620210[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl}-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester수율 38.8%

시약·촉매·용매 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 178418397HCID 178418397, 화합물촉매HCID 1140Toluene용매HCID 6228Dimethylformamide용매

반응 조건

온도
80 °C

실험 절차

A solution of (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (244 mg, 0.54 mmol), [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 (270 mg, 0.49 mmol) and aqueous K2CO3 (490 μl of a 2M solution, 0.98 mmol) in toluene (3 mL) and DMF (1 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (31 mg, 0.027 mmol) and PdCl2(dppf) (20 mg, 0.027 mmol) 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 (10-85% MeCN—H2O; 0.1% formic acid modifier) to afford [1-(2-{5-[6-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (149 mg, 0.19 mmol, 35% yield). 1H-NMR: 400 MHz, (DMSO-d6) δ: 11.82 (s, 1H), 11.79 (s, 1H), 8.21-8.16 (m, 2H), 7.92-7.79 (m, 8H), 7.62 (s, 1H), 7.54 (s, 1H), 7.31-7.29 (m, 2H), 5.10 (m, 2H), 4.09-4.07 (m, 2H), 3.82 (m, 4H), 3.54 (s, 6H), 2.20-1.85 (m, 10H), 0.95-0.86 (m, 12H). LCMS-ESI+: calc'd for C44H53N8O6: 789.4 (M+H+). Found: 789.2 (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 (10-85% MeCN—H2O; 0.1% formic acid modifier)

출처 및 근거

ORD 기록
ord-5eb3a1de6ed64bf2aaec6d8d704a26e8
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08822430B2

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