Hydrochloric Acid → HCID 67408688, compound

HRID 340804Notes

Reaction equation

HRID 340804 reaction equation
[C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:27])[C:15]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[NH:23][CH:22]=[CH:21]5)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:28][CH:29]2[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:3][CH:2]=1.[CH:46]1(B(O)O)[CH2:48][CH2:47]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl>CN(C1C=CN=CC=1)C.CC([O-])=O.CC([O-])=O.[Cu+2].C1(C)C=CC=CC=1>[C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:27])[C:15]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[N:23]([CH:46]4[CH2:48][CH2:47]4)[CH:22]=[CH:21]5)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:28][CH:29]2[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:5][CH:6]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 2724254Sodium bis(trimethylsilyl)amideHCID 2760897Cyclopropylboronic acidHCID 71074101HCID 71074101, compound

Product 1

HCID 67408688HCID 67408688, compound

Reagents, catalysts & solvents 3

HCID 8895Cupric acetateCatalystHCID 142844-(Dimethylamino)pyridineCatalystHCID 1140TolueneSolvent2×

Conditions

Temperature
95 °C

Procedure

A 10 mL flask was charged with ethyl 4-{[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-(1H-indol-5-yl)-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (0.080 g, 0.132 mmol), DMAP (0.048 g, 0.396 mmol), cyclopropylboronic acid (0.023 g, 0.264 mmol), and Cu(OAc)2 (4.8 mg, 0.026 mmol) under a nitrogen atmosphere. Toluene (1.3 mL) was added and the resulting suspension was treated with a 0.6 M solution of NaHMDS in toluene (0.220 mL, 0.132 mmol) dropwise via syringe. Dry air was purged into the reaction vessel, and the reaction was heated at 95° C. overnight. The dark reaction mixture was then cooled to ambient temperature and treated with 20 mL of 1 N HCl. The aqueous layer was separated and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting crude residue by preparative TLC (25% EtOAc/hexanes) furnished the title compound as a pale yellow residue. LCMS: calculated for C40H37F2N3O3 645.74, observed rule 646.2 (M+H)+ (Rt 3.03/4 min).

Workup

  1. customDry air
  2. customwas purged into the reaction vessel
  3. customThe dark reaction mixture
  4. temperaturewas then cooled to ambient temperature
  5. customThe aqueous layer was separated
  6. extractionextracted with EtOAc (2×25 mL)
  7. washThe combined organic layers were washed with brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customPurification of the resulting crude residue by preparative TLC (25% EtOAc/hexanes)

Sources & evidence

ORD record
ord-70edc5091bf9435db8957ce6ab804a6c
Source dataset
uspto-grants-2014_11
Patent number
US08895596B2

Reaction notes

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