Potassium Carbonate → 4-{2-[(2S,4S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-3H-naphth[1,2-d]imidazol-7-yl}-3-trifluoromethoxy-benzoic acid methyl ester

HRID 2203133Notes

Reaction equation

HRID 2203133 reaction equation
[CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][C:19]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25](B4OC(C)(C)C(C)(C)O4)[CH:26]=3)[C:20]=2[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:40][O:41][C:42](=[O:55])[C:43]1[CH:48]=[CH:47][C:46](Br)=[C:45]([O:50][C:51]([F:54])([F:53])[F:52])[CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.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]>[CH3:40][O:41][C:42](=[O:55])[C:43]1[CH:48]=[CH:47][C:46]([C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[C:20]2[N:21]=[C:17]([C@@H:12]4[CH2:13][C@H:14]([CH3:16])[CH2:15][N:11]4[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:39])[CH:6]([CH3:7])[CH3:8])[NH:18][C:19]=2[CH:29]=[CH:28]3)=[C:45]([O:50][C:51]([F:52])([F:54])[F:53])[CH:44]=1

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 59300634Methyl 4-bromo-3-(trifluoromethoxy)benzoateHCID 86700541((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

Product 1

HCID 867005404-{2-[(2S,4S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-3H-naphth[1,2-d]imidazol-7-yl}-3-trifluoromethoxy-benzoic acid methyl esterYield 97%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A solution of ((S)-2-methyl-1-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (250 mg, 0.48 mmol; Preparation 13), 4-bromo-3-trifluoromethoxy-benzoic acid methyl ester (140 mg, 0.47 mmol), and potassium carbonate (323 mg, 2.34 mmol) in toluene (2 mL) and water (0.5 mL) was purged with nitrogen for 5 min, then Pd(dppf)Cl2 (20.5 mg, 0.029 mmol) was added. The reaction mixture was stirred at 100° C. overnight, diluted with ethyl acetate (50 mL), washed with water (2×5 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (EtOAc/hexane 20 to 100%) to give the title intermediate (284 mg, 97% yield). (m/z): [M+H]+ calcd for C32H32F3N4O6 627.24 found 627.3.

Workup

  1. washwashed with water (2×5 mL)
  2. dry with materialThe organic layer was dried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. custompurified by silica gel chromatography (EtOAc/hexane 20 to 100%)

Sources & evidence

ORD record
ord-5966474fd4e548a4a2687e2dcea55ab7
Source dataset
uspto-grants-2016_06
Patent number
US09365549B2

Reaction notes

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