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 2176468Notes

Reaction equation

HRID 2176468 reaction equation
[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]

Participants

7

Reactant 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, compound

Product 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 esterYield 59%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-9db8b514274949bdad8904c7e4ae2dcd
Source dataset
uspto-grants-2015_06
Patent number
US09066944B2

Reaction notes

Loading…