Water → (R)-4-[5-(2-Chloro-4-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-3H-naphtho[1,2-d]imidazol-7-yl}-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester

HRID 2176468노트

반응식

HRID 2176468 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:35])[NH:21][C:22]3[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[C:25](Br)=[CH:24][C:23]=3[Cl:34])=[CH:16][N:15]=2)[C@H:10]([CH3:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39](=[O:75])[NH:40][C@H:41]([C:45]([N:47]1[CH2:51][C@@H:50]([CH3:52])[CH2:49][C@H:48]1[C:53]1[NH:57][C:56]2[C:58]3[C:63]([CH:64]=[CH:65][C:55]=2[N:54]=1)=[CH:62][C:61](B1OC(C)(C)C(C)(C)O1)=[CH:60][CH:59]=3)=[O:46])[CH:42]([CH3:44])[CH3:43].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=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].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:35])[NH:21][C:22]3[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[C:25]([C:61]4[CH:62]=[C:63]5[C:58](=[CH:59][CH:60]=4)[C:56]4[N:57]=[C:53]([C@@H:48]6[CH2:49][C@H:50]([CH3:52])[CH2:51][N:47]6[C:45](=[O:46])[C@@H:41]([NH:40][C:39]([O:38][CH3:37])=[O:75])[CH:42]([CH3:43])[CH3:44])[NH:54][C:55]=4[CH:65]=[CH:64]5)=[CH:24][C:23]=3[Cl:34])=[CH:16][N:15]=2)[C@H:10]([CH3:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

참가 물질

7

반응물 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 67494940(R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl esterHCID 178502430HCID 178502430, 화합물

생성물 1

HCID 86700555(R)-4-[5-(2-Chloro-4-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-3H-naphtho[1,2-d]imidazol-7-yl}-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester수율 59%

시약·촉매·용매 2

HCID 178418807HCID 178418807, 화합물촉매HCID 1140Toluene용매

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온도
90 °C

실험 절차

To a solution of (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.19 mmol) and ((S)-2-methyl-1-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (100 mg, 0.19 mmol) dissolved in toluene (1.19 mL) and water (0.43 mL) was added potassium carbonate (128 mg, 0.93 mmol). The reaction mixture was sparged with nitrogen for 15 min and Pd(dppf)Cl2 CH2Cl2 (13.6 mg, 0.017 mmol) was added. The reaction mixture was sparged with nitrogen, heated at 90° C. overnight, cooled to RT, diluted with EtOAc and washed with water and brine to produce a dark colored oil, which was purified by silica gel chromatography (24 g silica, 40% to 100% EtOAc/hexane) to produce the title intermediate (101 mg; 59% yield) as a yellow solid. (m/z): [M+H]+ calcd for C46H52ClF3N8O6 921.36 found 921.3.

후처리

  1. customThe reaction mixture was sparged with nitrogen for 15 min
  2. customThe reaction mixture was sparged with nitrogen
  3. temperaturecooled to RT
  4. additiondiluted with EtOAc
  5. washwashed with water and brine
  6. customto produce a dark colored oil, which
  7. customwas purified by silica gel chromatography (24 g silica, 40% to 100% EtOAc/hexane)

출처 및 근거

ORD 기록
ord-9db8b514274949bdad8904c7e4ae2dcd
출처 데이터셋
uspto-grants-2015_06
특허 번호
US09066944B2

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