Water → (R)-4-{5-[2-Chloro-4-(2-{(2S,4S)-1-[(S)-2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-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 2203148Notes

Reaction equation

HRID 2203148 reaction equation
[CH3:1][O:2][C:3](=[O:42])[NH:4][C@@H:5]([CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][C:16]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](B4OC(C)(C)C(C)(C)O4)[CH:23]=3)[C:17]=2[N:18]=1)=[O:7].[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62](=[O:77])[NH:63][C:64]3[CH:69]=[C:68]([O:70][C:71]([F:74])([F:73])[F:72])[C:67](Br)=[CH:66][C:65]=3[Cl:76])=[CH:58][N:57]=2)[C@H:52]([CH3:78])[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].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:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62](=[O:77])[NH:63][C:64]3[CH:69]=[C:68]([O:70][C:71]([F:74])([F:73])[F:72])[C:67]([C:22]4[CH:23]=[C:24]5[C:19](=[CH:20][CH:21]=4)[C:17]4[N:18]=[C:14]([C@@H:9]6[CH2:10][C@H:11]([CH3:13])[CH2:12][N:8]6[C:6](=[O:7])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:42])[CH:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)[NH:15][C:16]=4[CH:26]=[CH:25]5)=[CH:66][C:65]=3[Cl:76])=[CH:58][N:57]=2)[C@H:52]([CH3:78])[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]

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 86700557[(S)-2-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-naphth[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester

Product 1

HCID 86700556(R)-4-{5-[2-Chloro-4-(2-{(2S,4S)-1-[(S)-2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-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 92.4%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

To a mixture of [(S)-2-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-naphth[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester (80 mg, 0.10 mmol; Preparation 23) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (85 mg, 0.14 mmol) dissolved in toluene (0.92 mL) and water (0.34 mL) was added potassium carbonate (103 mg, 0.75 mmol). The reaction mixture was sparged under nitrogen and Pd(dppf)Cl2 CH2Cl2 (7.0 mg, 0.009 mmol) was added and the reaction mixture was heated to 90° C. overnight, cooled to RT, filtered through a combined pad of Celite® and silica gel and washed with EtOAc. The filtrate was washed with water and brine to produce a brownish colored solid, which was purified by silica chromatography (12 g column, 5-100% EtOAc/hexanes) to produce the title intermediate (89 mg, 60% yield) as a light colored solid. (m/z): [M+H]+ calcd for C48H54ClF3N8O8 963.37 found 963.5.

Workup

  1. customThe reaction mixture was sparged under nitrogen
  2. temperaturecooled to RT
  3. filtrationfiltered through a combined pad of Celite® and silica gel
  4. washwashed with EtOAc
  5. washThe filtrate was washed with water and brine
  6. customto produce a brownish colored solid, which
  7. customwas purified by silica chromatography (12 g column, 5-100% EtOAc/hexanes)

Sources & evidence

ORD record
ord-3170c804b8cb4f80aedfa4190c7a4a08
Source dataset
uspto-grants-2016_06
Patent number
US09365549B2

Reaction notes

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